- Email: [email protected]
Targeting ARG2 as a novel therapeutic approach for cancer
abstracts
Annals of Oncology 1971P
Pharmacokinetic/ pharmacodynamic (PK/PD) exposure-response characterization of GSK3359609 (GSK609) from INDUCE-1, a phase I open-label study
Background: GSK609 an agonist non-T cell depleting IgG4 monoclonal antibody (mAb) against inducible co-stimulatory receptor (ICOS) exhibits T cell mediated immune stimulating and anti-tumor activity. INDUCE-1 is the first in human study investigating GSK609 alone and in combinations which include pembrolizumab in select tumor types including recurrent/metastatic (R/M) HNSCC. Methods: Safety, PK, PD, and preliminary antitumor activity of GSK609 are being evaluated at doses from 0.001 to 10 mg/kg every 3 weeks (Q3W). Blood samples collected prior to dosing and on-study are evaluated for PK and PD effects on lymphocytes and ICOS receptor occupancy (RO). Tumor biopsies at Screening and Week 6 are evaluated for changes in tumor immune infiltrates (TIL) by a multiplexed immuno-fluorescence and gene expression platforms. Results: The GSK609 PK disposition shows low clearance, limited central volume of distribution, and mean systemic half-life of 19 days which is consistent with other humanized mAbs. Evidence of target engagement and tumor size reduction are observed in a R/M HNSCC expansion cohort (EC) at 0.3 mg/kg with 200 mg pembrolizumab. Dose and concentration-RO analyses suggest 0.1 mg/kg GSK609 maintains 70% RO on peripheral CD4þ and CD8þ T cells. Quantitative TIL evaluation of paired tumor biopsies demonstrates favorable immune microenvironment in the tumor at exposures observed in patients treated with 0.3mg/kg. TIL and tumor-based gene expression data demonstrate non-linear, dose-dependent changes in select immune activation markers. Exposure-response assessments reveal no difference in baseline-toWeek 9 target lesion change across exposures in the EC. Furthermore, cross-cohort pooled exposure-response analysis of Grade 2 AEs demonstrates similar safety outcomes across the exposures/doses. Additionally, population PK modeling suggests comparable exposures can be maintained by fixed dosing as well. Conclusions: The current data provide preliminary evidence of GSK609 target engagement and biological activity at clinically tolerable doses and support further exploration of the 0.3mg/kg or 24mg fixed dose. Clinical trial identification: NCT02723955 (Rel. 31March2016). Legal entity responsible for the study: GlaxoSmithKline. Funding: GlaxoSmithKline. Disclosure: M. Maio: Honoraria (self): BMS, MSD, Roche, Merck, Eli Lilly; Honoraria (institution), Patients’ fee to the University Hospital of Siena: BMS, MSD, AZ, Roche, Merck; Advisory / Consultancy: BMS, MSD, Roche, Merck, Eli Lilly; Travel / Accommodation / Expenses: BMS, MSD, Roche, Merck, Eli Lilly; Non-remunerated activity/ies, Press conferences: Merck, BMS. T. Bauer: Advisory / Consultancy, Self: Guardant Health; Loxo; Pfizer; Advisory / Consultancy, Institution: Ignyta; Moderna Therapeutics; Pfizer; Speaker Bureau / Expert testimony, Self: Bayer; Research grant / Funding (institution): Daiichi Sankyo; Medpacto, Inc.; Incyte; Mirati Therapeutics; MedImmune; Abbvie; AstraZeneca; Leap Therapeutics; MabVax; Stemline Therapeutics; Merck; Lilly; GlaxoSmithKline; Novartis, Pfizer; Genentech/Roche; Deciphera; Merrimack; Immunogen; Millennium; I; Travel / Accommodation / Expenses: Astellas Pharma; AstraZeneca; Celgene; Clovis Oncology; EMD Serono; Genentech; Lilly; Merck; Novartis; Pharmacyclics; Sysmex. D. Rischin: Advisory / Consultancy, All uncompensated : MSD, Regeneron, GSK, BMS; Research grant / Funding (institution): Regeneron, Roche, MSD, GSK, BMS; Travel / Accommodation / Expenses: MSD. V. Moreno: Advisory / Consultancy: Merck, BMS; Travel / Accommodation / Expenses: Regeneron/ Sanofi, BMS. J.M. Trigo Perez: Advisory / Consultancy: Regeneron/Sanofi, BMS; Speaker Bureau / Expert testimony: Regeneron/Sanofi, BMS; Travel / Accommodation / Expenses: Regeneron/Sanofi, BMS. M. Chisamore: Full / Part-time employment: Merck & Co. Inc; Shareholder / Stockholder / Stock options: Merck & Co. Inc. J. Sadik Shaik: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. F. Rigat: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. C. Ellis: Full / Parttime employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. H. Chen: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. R. Gagnon: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. S. Scherer: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. D. Turner: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. S. Yadavilli: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. M. Ballas: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. A. Hoos: Full / Parttime employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. E. Angevin: Advisory / Consultancy: Merck Sharp & Dohme, GlaxoSmithKline, Celgene Research, MedImmune; Travel / Accommodation / Expenses: AbbVie, Roche, Sanofi, Pfizer, MedImmune, Innate Pharma, Celgene, BMS; Research grant / Funding (institution): Abbvie, Aduro, Agios, Amgen,
Volume 30 | Supplement 5 | October 2019
1972P
In vitro functional interrogation of viable circulating tumor associated cells (C-TACs) for evaluating platin resistance
S. Schuster, D. Akolkar, S. Patil, D. Patil, V. Datta, A. Srinivasan, R. Datar Research and Innovations, Datar Cancer Genetics Limited, Nasik, India
1
Background: Platins are used extensively to treat Solid Organ Cancers like Ovarian, Breast, Colorectal, Lung, Pancreatic and Bladder Cancer. Eventually however, most cancer patients develop resistance to these treatments. As presently, no assay is available to non-invasively determine the onset of resistance to platinum drugs, the lethal evolution is usually silent. We show that apoptosis resistant Circulating Tumor Associated Cells (C-TACs) can be isolated and functionally interrogated in vitro to determine response / resistance to Platins in real time by chemo-sensitivity. Methods: We evaluated the chemo-sensitivity / resistance profile of C-TACs obtained from 256 patients with confirmed diagnosis of Breast, Ovarian, Colorectal, Pancreatic, or Lung cancer; 207 (80.8%) patients were refractory to Platins, 49 (19.2%) were treatment naı¨ve and 36 (14.0%) of C-TAC samples were compared with corresponding Tumor Derived Cells (TDCs). Results: Out of 256 samples of venous blood examined, more than 5000 C-TACs could be harvested in 244 (95.0%) samples. 182 (88.0%) samples from the refractory cohort showed chemo resistance to Platins, 16 (34.0%) of samples from treatment naı¨ve samples showed Platin resistance and 29 (85.2%) concurrently analyzed C-TAC samples showed chemo resistance to Platins corresponding to identical resistance in TDCs. Conclusions: Functional interrogation of C-TACs by in vitro chemo-sensitivity analysis provides an accurate non-invasive method to determine Platin resistance in solid organ cancers. Legal entity responsible for the study: The authors. Funding: Datar Cancer Genetics Limited. Disclosure: S. Schuster: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. S. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Officer / Board of Directors: Datar Cancer Genetics Limited.
1973P
Targeting ARG2 as a novel therapeutic approach for cancer
nczak, M. Welzer, M.M. Grzybowski, J. Pe˛czkowicz-Szyszka, P. Wolska, P.S. Sta E. Nikolaev, A.M. Siwi nska, R. Błaszczyk, B. Borek, M. Dzie˛gielewski, A. Gzik, J. Nowicka, J. Brzezi nska, K. Je˛drzejczak, J. Chrzanowski, A. Gołe˛biowski, J. Olczak, K. Dzwonek, P. Dobrza nski Department of Biology, OncoArendi Therapeutics SA, Warsaw, Poland Background: Immunotherapies are considered the most promising therapeutic approach for cancer and the immunosuppressive activity of ARG1 has been recognized as an important mechanism of the tumor immune evasion. This prompted the development of arginase inhibitors, which in preclinical models, enhanced antitumor immunity as a monotherapy and in combination with other immune checkpoint inhibitors. On the other hand, ARG2, but not ARG1, is highly expressed in neoplastic cells in many tumors and its expression is correlated with malignant phenotype. Preclinical studies confirmed that ARG2 promotes the proliferation of cancer cells and the growth of tumor xenografts independently of its immunosuppressive activity. Generation of polyamines to facilitate the growth of hypoxic and nutrient-deprived tumors, as well as specific metabolic adaptations including increased reliance on protein catabolism are the major mechanisms underlying the tumorigenic activity of ARG2. Hence, the tumor cell intrinsic activity of ARG2 represents an attractive intracellular target for novel therapies with arginase inhibitors. Methods: The compound activity was determined using human ARG1 and ARG2, and in CHO-K cells expressing ARG1 and ARG2. ARG1 and ARG2 expression in cancer cell lines and dissected tumors was assessed by WB and qPCR. CellTiter-Glo was used to assess the antiproliferative activity of the compound. In vivo antitumor activity was evaluated in murine CT26 (syngeneic) and human K562 (xenograft) subcutaneous mouse models. Results: The expression of the endogenous ARG2 was confirmed in multiple human cancer cell lines and xenografts. We developed a highly potent dual ARG1 and ARG2 inhibitor, OATD-02, with a good cellular activity. We demonstrated that OATD-02 inhibited proliferation of multiple human cancer cell lines expressing ARG2 and suppressed the growth of human xenografts. OATD-02 also strongly inhibited the growth of the syngeneic CT26 tumors. Conclusions: OATD-02, a potent ARG1 and ARG2 inhibitor, exerts its antitumor efficacy not only by the reactivation of the immune response but also by directly suppressing the ARG2-dependent proliferation of cancerous cells. Thus, OATD-02 is a very promising compound for the treatment of hypoxic tumors which are particularly resistant to therapies.
doi:10.1093/annonc/mdz268 | v793
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M. Maio1, S.L. Groenland2, T. Bauer3, D. Rischin4, I. Gardeazabal5, V. Moreno6, J.M. Trigo Perez7, M. Chisamore8, J. Sadik Shaik9, F. Rigat10, C. Ellis11, H. Chen12, R. Gagnon12, S. Scherer13, D. Turner9, S. Yadavilli13, M. Ballas11, A. Hoos11, E. Angevin14 1 Center for Immuno-Oncology, Instituto Toscano Tumori, Azienda Ospedaliera Universitaria Senese - Santa Maria delle Scotte, Siena, Italy, 2Pharmacy & Pharmacology Department, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), Amsterdam, Netherlands, 3Hematology/Oncology, Sarah Cannon Research Institute, Nashville, TN, USA, 4Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, 5Medical Oncology Dept., Vall d’Hebron University Hospital, Barcelona, Spain, 6Clinical Research Phase 1 Trials Unit, START Madrid-FJD, Madrid, Spain, 7Medical Oncology, Hospital Universitario Virgen de la Victoria, Malaga, Spain, 8Oncology Early Clinical Development, Merck Sharp & Dohme Corp. USA, Whitehouse Station, NJ, USA, 9Clinical Pharmacology, GlaxoSmithKline, Collegeville, PA, USA, 10Clinical Statistics, GlaxoSmithKline, Stevenage, UK, 11Oncology Clinical Development, GlaxoSmithKline USA, Collegeville, PA, USA, 12 Clinical Statistics, GlaxoSmithKline, Collegeville, PA, USA, 13Clinical Biomarkers, GlaxoSmithKline USA, Collegeville, PA, USA, 14Drug Development Department (DITEP), Gustave Roussy - Cancer Campus, Villejuif, France
Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 bio. All other authors have declared no conflicts of interest.
abstracts Legal entity responsible for the study: OncoArendi Therapeutics SA. Funding: National Centre for Research and Development in Poland. Disclosure: M.M. Grzybowski: Full / Part-time employment: OncoArendi Therapeutics SA. J.
1974P
MPS1 and PLK1 as new therapy targets in TP53 mutated solid tumors
administered. The model was applied to predict exposure combinations that result in tumor eradication using the TSE. Results: The developed model captured experimental data from all treatment groups adequately, with the parameter estimates taking biologically reasonable values. Model simulation showed that tumor eradication is observed at total radiation dose of 110 Gy, which is reduced to 80 or 30 Gy with co-administration of 25 or 100 mg/kg of a radiosensitizer. Conclusions: The new model can describe different tumor dynamics including tumor eradication and tumor regrowth with different rates. The proposed model can be expanded for radiation in combination with chemical interventions or immunotherapy. The model and TSE can be applied to generate treatment predictions for different dosing schedules or determining drug synergies. The translational utility of the TSE concept is currently under investigation. Legal entity responsible for the study: Merck Healthcare KGaA. Funding: Tim Cardilin was supported by an education Grant from Merck Healthcare KGaA, Darmstadt, Germany. This work was also partially funded by the Swedish Foundation for Strategic Research (Grant no. AM13-0046). Disclosure: S. El Bawab: Full / Part-time employment: Merck Healthcare KGaA. A. Zimmermann: Full / Part-time employment: Merck Healthcare KGaA. F. Lignet: Full / Part-time employment: Merck Healthcare KGaA. All authors have declared no conflicts of interest.
B. Gyorffy, A. Nagy, A. Osz Second Department of Pediatrics, Semmelweis University, Budapest, Hungary, 1976P Background: The tumor suppressor TP53 is the most frequently mutated gene in solid tumors. Although TP53 decides cell fate and governs initiation of apoptosis, inhibitors targeting mutant TP53 did not yet reached clinical use. Our goal was to identify new potential therapeutic targets in TP53 mutant solid tumors by in silico analysis of multiple large, independent next-generation sequencing and gene chip datasets. Methods: First, gene expression and mutation data from multiple solid tumors were collected from TCGA and METABRIC databases. Samples were separated based on TP53 mutation status, mutational type and tumor type to identify targetable genes. Differential gene expression was compared using Mann-Whitney test between the mutated (disruptive mutations only) and wild type patient cohorts across all genes. Then, the prognostic value of identified genes was validated in a gene chip-based dataset obtained from the GEO repository. Survival analysis was performed using Cox proportional hazards regression. Significance threshold was set at p < 0.01. Finally, False Discovery Rate was computed to correct for multiple hypothesis testing. Results: The TCGA dataset include 9,720 patients (21 different cancer types), the Metabric dataset (breast cancer) 1,399 patients, and the GEO dataset (breast, lung, and brain tumors) 7,386 patients. Only genes with higher expression in the TP53 mutant cohort were selected and the list of the top targets was further filtered to include only druggable kinases. The best performing kinases include MPS1 (p ¼ 2.9E-58, FC ¼ 2.82), PLK1 (p ¼ 2.6E-55, FC ¼ 2.55), MELK (p ¼ 5.2E-54, FC ¼ 2.81), and AURKB (p ¼ 2E-53, FC ¼ 3.23). Each of these kinases had a significant prognostic power as well. Of the top 2 (MPS1 and PLK1), both have multiple inhibitors available (for other indications) with PLK1 closest to the clinical use. Conclusions: Our results suggest that MPS1 (monopolar spindle 1 kinase) and PLK1 (polo like kinase 1) kinases are the strongest druggable targets in TP53 mutant solid tumors. Legal entity responsible for the study: Semmelweis University. Funding: National Research, Development and Innovation Office, Hungary. Disclosure: All authors have declared no conflicts of interest.
1975P
The tumor static exposure (TSE) concept & utility: Application to combination treatment of radiation and radiosensitizing agent in tumor xenograft experiments
S. El Bawab1, T. Cardilin2, M. Jirstrand2, A. Zimmermann3, F. Lignet1, J. Gabrielsson4 Translational Medicine, Merck Healthcare KGaA, Darmstadt, Germany, 2Department Systems and Data Analysis, Fraunhofer-Chalmers Centre, Go¨teborg, Sweden, 3 Translational Innovation Platform Oncology, Merck Healthcare KGaA, Darmstadt, Germany, 4Department of Biomedical Science and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
1
Background: We present a pharmacodynamic model that describes the tumor volume evolution during and after treatment with radiation and in combination with a radiosensitizing agent. A key contribution is the inclusion of a long-term radiation effect, which allows the model to describe distinct tumor behaviors including tumor eradication and tumor regrowth with different growth rates. Additionally, we introduce the concept of TSE (Tumor Static Exposure), the exposures of one or multiple compounds that result in tumor stasis and provide an example of its utility for optimizing drug combinations in oncology. Methods: The model was challenged with data from four treatment groups (Vehicle, radiation, radiation þ radiosensitizer 25 or 100 mg/kg) in xenograft study using a clinically-relevant administration schedule (6 weeks treatment, 5 days on/2 days off) and a mixed-effects approach was used for model-fitting. The model incorporated a permanent inhibition of the natural growth rate. This step was required to capture the complete tumor eradication and the observed tumor regrowth with different rates with animals having slower regrowth compared to control animals. The presence of a radiosensitizer will lead to the same tumor evolution as if a higher dose of radiation had been
v794 | Translational Research
General methodology to optimize tumor treating fields delivery utilizing numerical simulations
N. Urman1, Z. Bomzon1, H.S. Hershkovich1, E.D. Kirson1, A. Naveh1, R. Shamir1, E. Fedorov1, C. Wenger2, U. Weinberg1 1 Research and Development, Novocure, Haifa, Israel, 2Research and Development, Novocure GmbH, Lucerne, Switzerland Background: Tumor Treating Fields (TTFields) are intermediate frequency, alternating electric fields that non-invasively treat cancer. Transducer arrays positioned on the skin in proximity to the targeted tumor transmit TTFields. A post-hoc analysis [Ballo et al. Red Jour. 2019 In Press] has shown that increased patient usage (percent of time on active treatment) and intensity of TTFields delivery direct to the tumor improved survival. Optimal array positioning may enhance TTFields intensity at the tumor site to improve patient experience and survival. Minimization of array exposure area would enhance patient comfort levels and usage to improve survival. Optimizing TTFields delivery and distribution depends on array positioning and geometry, patient anatomy, and the heterogeneous electrical properties of different tissues. We present methodology to optimize TTFields delivery using numerical simulations. Methods: TTFields delivery to the brain, lung, and abdomen utilizing representative computational models was investigated. The effects of transducer array size and position on field distribution within the phantoms was analyzed, and an approach to optimize TTFields delivery was developed. Results: Field intensity was typically the greatest in between arrays, with larger arrays transmitting higher field power. Anatomical features, such as bones (spine) or a resection cavity significantly influenced field intensity within this region. A generalized methodology to optimize TTFields delivery for improved patient care was based on: (1) Striking a balance between maximal field intensity (largest arrays feasible) and minimal skin exposure to arrays in the disease area; (2) Positioning virtual arrays on a representative, computational patient model to test tumor localization between arrays, to simulate TTFields delivery to patient, and to assess optimal delivery; and (3) Applying an iterative algorithm to shift arrays around their initial positions until field intensity is maximized directly to the tumor bed. Conclusions: A generalized treatment methodology as presented by these data will optimize TTFields delivery to the tumor site. Effective TTFields treatment planning is expected to improve patient outcomes. Legal entity responsible for the study: Novocure. Funding: Novocure. Disclosure: N. Urman: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. Z. Bomzon: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. H.S. Hershkovich: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. E.D. Kirson: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. A. Naveh: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. R. Shamir: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. E. Fedorov: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. C. Wenger: Full / Parttime employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. U. Weinberg: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure.
1977TiP
The Australian Exceptional Responders Program: A national collaboration
M. Barnet1, S. Pathmanandavel1, L. McCarthy2, C. Goodnow3, A. Joshua1 Medical Oncology Department, The Kinghorn Cancer Centre, Darlinghurst, Australia, 2 Clinical Trials, St Vincent’s Hospital Sydney, Darlinghurst, Australia, 3Immunogenomics, The Garvan Institute of Medical Research, Darlinghurst, Australia,
1
Background: Analysis of outliers leads to breakthroughs in oncology. Examples of this include pan-approval for anti-PD1 therapy in mismatch repair deficient tumours and
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz268.100/5577207 by guest on 24 October 2019
Pe˛czkowicz-Szyszka: Full / Part-time employment: OncoArendi Therapeutics SA. P. Wolska: Full / Part-time employment: OncoArendi Therapeutics SA. P.S. Sta nczak: Full / Part-time employment: OncoArendi Therapeutics SA. M. Welzer: Full / Part-time employment: OncoArendi Therapeutics SA. E. Nikolaev: Full / Part-time employment: OncoArendi Therapeutics SA. A.M. Siwi nska: Full / Part-time employment: OncoArendi Therapeutics SA. R. Błaszczyk: Full / Part-time employment: OncoArendi Therapeutics SA. B. Borek: Full / Part-time employment: OncoArendi Therapeutics SA. M. Dzie˛gielewski: Full / Part-time employment: OncoArendi Therapeutics SA. A. Gzik: Full / Parttime employment: OncoArendi Therapeutics SA. J. Nowicka: Full / Part-time employment: OncoArendi Therapeutics SA. J. Brzezi nska: Full / Part-time employment: OncoArendi Therapeutics SA. K. Je˛drzejczak: Full / Part-time employment: OncoArendi Therapeutics SA. J. Chrzanowski: Full / Part-time employment: OncoArendi Therapeutics SA. A. Gołe˛biowski: Leadership role, Full / Parttime employment: OncoArendi Therapeutics SA. J. Olczak: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. P. Dobrza nski: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. All other authors have declared no conflicts of interest.
Annals of Oncology
Annals of Oncology 1971P
Pharmacokinetic/ pharmacodynamic (PK/PD) exposure-response characterization of GSK3359609 (GSK609) from INDUCE-1, a phase I open-label study
Background: GSK609 an agonist non-T cell depleting IgG4 monoclonal antibody (mAb) against inducible co-stimulatory receptor (ICOS) exhibits T cell mediated immune stimulating and anti-tumor activity. INDUCE-1 is the first in human study investigating GSK609 alone and in combinations which include pembrolizumab in select tumor types including recurrent/metastatic (R/M) HNSCC. Methods: Safety, PK, PD, and preliminary antitumor activity of GSK609 are being evaluated at doses from 0.001 to 10 mg/kg every 3 weeks (Q3W). Blood samples collected prior to dosing and on-study are evaluated for PK and PD effects on lymphocytes and ICOS receptor occupancy (RO). Tumor biopsies at Screening and Week 6 are evaluated for changes in tumor immune infiltrates (TIL) by a multiplexed immuno-fluorescence and gene expression platforms. Results: The GSK609 PK disposition shows low clearance, limited central volume of distribution, and mean systemic half-life of 19 days which is consistent with other humanized mAbs. Evidence of target engagement and tumor size reduction are observed in a R/M HNSCC expansion cohort (EC) at 0.3 mg/kg with 200 mg pembrolizumab. Dose and concentration-RO analyses suggest 0.1 mg/kg GSK609 maintains 70% RO on peripheral CD4þ and CD8þ T cells. Quantitative TIL evaluation of paired tumor biopsies demonstrates favorable immune microenvironment in the tumor at exposures observed in patients treated with 0.3mg/kg. TIL and tumor-based gene expression data demonstrate non-linear, dose-dependent changes in select immune activation markers. Exposure-response assessments reveal no difference in baseline-toWeek 9 target lesion change across exposures in the EC. Furthermore, cross-cohort pooled exposure-response analysis of Grade 2 AEs demonstrates similar safety outcomes across the exposures/doses. Additionally, population PK modeling suggests comparable exposures can be maintained by fixed dosing as well. Conclusions: The current data provide preliminary evidence of GSK609 target engagement and biological activity at clinically tolerable doses and support further exploration of the 0.3mg/kg or 24mg fixed dose. Clinical trial identification: NCT02723955 (Rel. 31March2016). Legal entity responsible for the study: GlaxoSmithKline. Funding: GlaxoSmithKline. Disclosure: M. Maio: Honoraria (self): BMS, MSD, Roche, Merck, Eli Lilly; Honoraria (institution), Patients’ fee to the University Hospital of Siena: BMS, MSD, AZ, Roche, Merck; Advisory / Consultancy: BMS, MSD, Roche, Merck, Eli Lilly; Travel / Accommodation / Expenses: BMS, MSD, Roche, Merck, Eli Lilly; Non-remunerated activity/ies, Press conferences: Merck, BMS. T. Bauer: Advisory / Consultancy, Self: Guardant Health; Loxo; Pfizer; Advisory / Consultancy, Institution: Ignyta; Moderna Therapeutics; Pfizer; Speaker Bureau / Expert testimony, Self: Bayer; Research grant / Funding (institution): Daiichi Sankyo; Medpacto, Inc.; Incyte; Mirati Therapeutics; MedImmune; Abbvie; AstraZeneca; Leap Therapeutics; MabVax; Stemline Therapeutics; Merck; Lilly; GlaxoSmithKline; Novartis, Pfizer; Genentech/Roche; Deciphera; Merrimack; Immunogen; Millennium; I; Travel / Accommodation / Expenses: Astellas Pharma; AstraZeneca; Celgene; Clovis Oncology; EMD Serono; Genentech; Lilly; Merck; Novartis; Pharmacyclics; Sysmex. D. Rischin: Advisory / Consultancy, All uncompensated : MSD, Regeneron, GSK, BMS; Research grant / Funding (institution): Regeneron, Roche, MSD, GSK, BMS; Travel / Accommodation / Expenses: MSD. V. Moreno: Advisory / Consultancy: Merck, BMS; Travel / Accommodation / Expenses: Regeneron/ Sanofi, BMS. J.M. Trigo Perez: Advisory / Consultancy: Regeneron/Sanofi, BMS; Speaker Bureau / Expert testimony: Regeneron/Sanofi, BMS; Travel / Accommodation / Expenses: Regeneron/Sanofi, BMS. M. Chisamore: Full / Part-time employment: Merck & Co. Inc; Shareholder / Stockholder / Stock options: Merck & Co. Inc. J. Sadik Shaik: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. F. Rigat: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. C. Ellis: Full / Parttime employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. H. Chen: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. R. Gagnon: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. S. Scherer: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. D. Turner: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. S. Yadavilli: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. M. Ballas: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. A. Hoos: Full / Parttime employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. E. Angevin: Advisory / Consultancy: Merck Sharp & Dohme, GlaxoSmithKline, Celgene Research, MedImmune; Travel / Accommodation / Expenses: AbbVie, Roche, Sanofi, Pfizer, MedImmune, Innate Pharma, Celgene, BMS; Research grant / Funding (institution): Abbvie, Aduro, Agios, Amgen,
Volume 30 | Supplement 5 | October 2019
1972P
In vitro functional interrogation of viable circulating tumor associated cells (C-TACs) for evaluating platin resistance
S. Schuster, D. Akolkar, S. Patil, D. Patil, V. Datta, A. Srinivasan, R. Datar Research and Innovations, Datar Cancer Genetics Limited, Nasik, India
1
Background: Platins are used extensively to treat Solid Organ Cancers like Ovarian, Breast, Colorectal, Lung, Pancreatic and Bladder Cancer. Eventually however, most cancer patients develop resistance to these treatments. As presently, no assay is available to non-invasively determine the onset of resistance to platinum drugs, the lethal evolution is usually silent. We show that apoptosis resistant Circulating Tumor Associated Cells (C-TACs) can be isolated and functionally interrogated in vitro to determine response / resistance to Platins in real time by chemo-sensitivity. Methods: We evaluated the chemo-sensitivity / resistance profile of C-TACs obtained from 256 patients with confirmed diagnosis of Breast, Ovarian, Colorectal, Pancreatic, or Lung cancer; 207 (80.8%) patients were refractory to Platins, 49 (19.2%) were treatment naı¨ve and 36 (14.0%) of C-TAC samples were compared with corresponding Tumor Derived Cells (TDCs). Results: Out of 256 samples of venous blood examined, more than 5000 C-TACs could be harvested in 244 (95.0%) samples. 182 (88.0%) samples from the refractory cohort showed chemo resistance to Platins, 16 (34.0%) of samples from treatment naı¨ve samples showed Platin resistance and 29 (85.2%) concurrently analyzed C-TAC samples showed chemo resistance to Platins corresponding to identical resistance in TDCs. Conclusions: Functional interrogation of C-TACs by in vitro chemo-sensitivity analysis provides an accurate non-invasive method to determine Platin resistance in solid organ cancers. Legal entity responsible for the study: The authors. Funding: Datar Cancer Genetics Limited. Disclosure: S. Schuster: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. S. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Officer / Board of Directors: Datar Cancer Genetics Limited.
1973P
Targeting ARG2 as a novel therapeutic approach for cancer
nczak, M. Welzer, M.M. Grzybowski, J. Pe˛czkowicz-Szyszka, P. Wolska, P.S. Sta E. Nikolaev, A.M. Siwi nska, R. Błaszczyk, B. Borek, M. Dzie˛gielewski, A. Gzik, J. Nowicka, J. Brzezi nska, K. Je˛drzejczak, J. Chrzanowski, A. Gołe˛biowski, J. Olczak, K. Dzwonek, P. Dobrza nski Department of Biology, OncoArendi Therapeutics SA, Warsaw, Poland Background: Immunotherapies are considered the most promising therapeutic approach for cancer and the immunosuppressive activity of ARG1 has been recognized as an important mechanism of the tumor immune evasion. This prompted the development of arginase inhibitors, which in preclinical models, enhanced antitumor immunity as a monotherapy and in combination with other immune checkpoint inhibitors. On the other hand, ARG2, but not ARG1, is highly expressed in neoplastic cells in many tumors and its expression is correlated with malignant phenotype. Preclinical studies confirmed that ARG2 promotes the proliferation of cancer cells and the growth of tumor xenografts independently of its immunosuppressive activity. Generation of polyamines to facilitate the growth of hypoxic and nutrient-deprived tumors, as well as specific metabolic adaptations including increased reliance on protein catabolism are the major mechanisms underlying the tumorigenic activity of ARG2. Hence, the tumor cell intrinsic activity of ARG2 represents an attractive intracellular target for novel therapies with arginase inhibitors. Methods: The compound activity was determined using human ARG1 and ARG2, and in CHO-K cells expressing ARG1 and ARG2. ARG1 and ARG2 expression in cancer cell lines and dissected tumors was assessed by WB and qPCR. CellTiter-Glo was used to assess the antiproliferative activity of the compound. In vivo antitumor activity was evaluated in murine CT26 (syngeneic) and human K562 (xenograft) subcutaneous mouse models. Results: The expression of the endogenous ARG2 was confirmed in multiple human cancer cell lines and xenografts. We developed a highly potent dual ARG1 and ARG2 inhibitor, OATD-02, with a good cellular activity. We demonstrated that OATD-02 inhibited proliferation of multiple human cancer cell lines expressing ARG2 and suppressed the growth of human xenografts. OATD-02 also strongly inhibited the growth of the syngeneic CT26 tumors. Conclusions: OATD-02, a potent ARG1 and ARG2 inhibitor, exerts its antitumor efficacy not only by the reactivation of the immune response but also by directly suppressing the ARG2-dependent proliferation of cancerous cells. Thus, OATD-02 is a very promising compound for the treatment of hypoxic tumors which are particularly resistant to therapies.
doi:10.1093/annonc/mdz268 | v793
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M. Maio1, S.L. Groenland2, T. Bauer3, D. Rischin4, I. Gardeazabal5, V. Moreno6, J.M. Trigo Perez7, M. Chisamore8, J. Sadik Shaik9, F. Rigat10, C. Ellis11, H. Chen12, R. Gagnon12, S. Scherer13, D. Turner9, S. Yadavilli13, M. Ballas11, A. Hoos11, E. Angevin14 1 Center for Immuno-Oncology, Instituto Toscano Tumori, Azienda Ospedaliera Universitaria Senese - Santa Maria delle Scotte, Siena, Italy, 2Pharmacy & Pharmacology Department, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), Amsterdam, Netherlands, 3Hematology/Oncology, Sarah Cannon Research Institute, Nashville, TN, USA, 4Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, 5Medical Oncology Dept., Vall d’Hebron University Hospital, Barcelona, Spain, 6Clinical Research Phase 1 Trials Unit, START Madrid-FJD, Madrid, Spain, 7Medical Oncology, Hospital Universitario Virgen de la Victoria, Malaga, Spain, 8Oncology Early Clinical Development, Merck Sharp & Dohme Corp. USA, Whitehouse Station, NJ, USA, 9Clinical Pharmacology, GlaxoSmithKline, Collegeville, PA, USA, 10Clinical Statistics, GlaxoSmithKline, Stevenage, UK, 11Oncology Clinical Development, GlaxoSmithKline USA, Collegeville, PA, USA, 12 Clinical Statistics, GlaxoSmithKline, Collegeville, PA, USA, 13Clinical Biomarkers, GlaxoSmithKline USA, Collegeville, PA, USA, 14Drug Development Department (DITEP), Gustave Roussy - Cancer Campus, Villejuif, France
Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 bio. All other authors have declared no conflicts of interest.
abstracts Legal entity responsible for the study: OncoArendi Therapeutics SA. Funding: National Centre for Research and Development in Poland. Disclosure: M.M. Grzybowski: Full / Part-time employment: OncoArendi Therapeutics SA. J.
1974P
MPS1 and PLK1 as new therapy targets in TP53 mutated solid tumors
administered. The model was applied to predict exposure combinations that result in tumor eradication using the TSE. Results: The developed model captured experimental data from all treatment groups adequately, with the parameter estimates taking biologically reasonable values. Model simulation showed that tumor eradication is observed at total radiation dose of 110 Gy, which is reduced to 80 or 30 Gy with co-administration of 25 or 100 mg/kg of a radiosensitizer. Conclusions: The new model can describe different tumor dynamics including tumor eradication and tumor regrowth with different rates. The proposed model can be expanded for radiation in combination with chemical interventions or immunotherapy. The model and TSE can be applied to generate treatment predictions for different dosing schedules or determining drug synergies. The translational utility of the TSE concept is currently under investigation. Legal entity responsible for the study: Merck Healthcare KGaA. Funding: Tim Cardilin was supported by an education Grant from Merck Healthcare KGaA, Darmstadt, Germany. This work was also partially funded by the Swedish Foundation for Strategic Research (Grant no. AM13-0046). Disclosure: S. El Bawab: Full / Part-time employment: Merck Healthcare KGaA. A. Zimmermann: Full / Part-time employment: Merck Healthcare KGaA. F. Lignet: Full / Part-time employment: Merck Healthcare KGaA. All authors have declared no conflicts of interest.
B. Gyorffy, A. Nagy, A. Osz Second Department of Pediatrics, Semmelweis University, Budapest, Hungary, 1976P Background: The tumor suppressor TP53 is the most frequently mutated gene in solid tumors. Although TP53 decides cell fate and governs initiation of apoptosis, inhibitors targeting mutant TP53 did not yet reached clinical use. Our goal was to identify new potential therapeutic targets in TP53 mutant solid tumors by in silico analysis of multiple large, independent next-generation sequencing and gene chip datasets. Methods: First, gene expression and mutation data from multiple solid tumors were collected from TCGA and METABRIC databases. Samples were separated based on TP53 mutation status, mutational type and tumor type to identify targetable genes. Differential gene expression was compared using Mann-Whitney test between the mutated (disruptive mutations only) and wild type patient cohorts across all genes. Then, the prognostic value of identified genes was validated in a gene chip-based dataset obtained from the GEO repository. Survival analysis was performed using Cox proportional hazards regression. Significance threshold was set at p < 0.01. Finally, False Discovery Rate was computed to correct for multiple hypothesis testing. Results: The TCGA dataset include 9,720 patients (21 different cancer types), the Metabric dataset (breast cancer) 1,399 patients, and the GEO dataset (breast, lung, and brain tumors) 7,386 patients. Only genes with higher expression in the TP53 mutant cohort were selected and the list of the top targets was further filtered to include only druggable kinases. The best performing kinases include MPS1 (p ¼ 2.9E-58, FC ¼ 2.82), PLK1 (p ¼ 2.6E-55, FC ¼ 2.55), MELK (p ¼ 5.2E-54, FC ¼ 2.81), and AURKB (p ¼ 2E-53, FC ¼ 3.23). Each of these kinases had a significant prognostic power as well. Of the top 2 (MPS1 and PLK1), both have multiple inhibitors available (for other indications) with PLK1 closest to the clinical use. Conclusions: Our results suggest that MPS1 (monopolar spindle 1 kinase) and PLK1 (polo like kinase 1) kinases are the strongest druggable targets in TP53 mutant solid tumors. Legal entity responsible for the study: Semmelweis University. Funding: National Research, Development and Innovation Office, Hungary. Disclosure: All authors have declared no conflicts of interest.
1975P
The tumor static exposure (TSE) concept & utility: Application to combination treatment of radiation and radiosensitizing agent in tumor xenograft experiments
S. El Bawab1, T. Cardilin2, M. Jirstrand2, A. Zimmermann3, F. Lignet1, J. Gabrielsson4 Translational Medicine, Merck Healthcare KGaA, Darmstadt, Germany, 2Department Systems and Data Analysis, Fraunhofer-Chalmers Centre, Go¨teborg, Sweden, 3 Translational Innovation Platform Oncology, Merck Healthcare KGaA, Darmstadt, Germany, 4Department of Biomedical Science and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
1
Background: We present a pharmacodynamic model that describes the tumor volume evolution during and after treatment with radiation and in combination with a radiosensitizing agent. A key contribution is the inclusion of a long-term radiation effect, which allows the model to describe distinct tumor behaviors including tumor eradication and tumor regrowth with different growth rates. Additionally, we introduce the concept of TSE (Tumor Static Exposure), the exposures of one or multiple compounds that result in tumor stasis and provide an example of its utility for optimizing drug combinations in oncology. Methods: The model was challenged with data from four treatment groups (Vehicle, radiation, radiation þ radiosensitizer 25 or 100 mg/kg) in xenograft study using a clinically-relevant administration schedule (6 weeks treatment, 5 days on/2 days off) and a mixed-effects approach was used for model-fitting. The model incorporated a permanent inhibition of the natural growth rate. This step was required to capture the complete tumor eradication and the observed tumor regrowth with different rates with animals having slower regrowth compared to control animals. The presence of a radiosensitizer will lead to the same tumor evolution as if a higher dose of radiation had been
v794 | Translational Research
General methodology to optimize tumor treating fields delivery utilizing numerical simulations
N. Urman1, Z. Bomzon1, H.S. Hershkovich1, E.D. Kirson1, A. Naveh1, R. Shamir1, E. Fedorov1, C. Wenger2, U. Weinberg1 1 Research and Development, Novocure, Haifa, Israel, 2Research and Development, Novocure GmbH, Lucerne, Switzerland Background: Tumor Treating Fields (TTFields) are intermediate frequency, alternating electric fields that non-invasively treat cancer. Transducer arrays positioned on the skin in proximity to the targeted tumor transmit TTFields. A post-hoc analysis [Ballo et al. Red Jour. 2019 In Press] has shown that increased patient usage (percent of time on active treatment) and intensity of TTFields delivery direct to the tumor improved survival. Optimal array positioning may enhance TTFields intensity at the tumor site to improve patient experience and survival. Minimization of array exposure area would enhance patient comfort levels and usage to improve survival. Optimizing TTFields delivery and distribution depends on array positioning and geometry, patient anatomy, and the heterogeneous electrical properties of different tissues. We present methodology to optimize TTFields delivery using numerical simulations. Methods: TTFields delivery to the brain, lung, and abdomen utilizing representative computational models was investigated. The effects of transducer array size and position on field distribution within the phantoms was analyzed, and an approach to optimize TTFields delivery was developed. Results: Field intensity was typically the greatest in between arrays, with larger arrays transmitting higher field power. Anatomical features, such as bones (spine) or a resection cavity significantly influenced field intensity within this region. A generalized methodology to optimize TTFields delivery for improved patient care was based on: (1) Striking a balance between maximal field intensity (largest arrays feasible) and minimal skin exposure to arrays in the disease area; (2) Positioning virtual arrays on a representative, computational patient model to test tumor localization between arrays, to simulate TTFields delivery to patient, and to assess optimal delivery; and (3) Applying an iterative algorithm to shift arrays around their initial positions until field intensity is maximized directly to the tumor bed. Conclusions: A generalized treatment methodology as presented by these data will optimize TTFields delivery to the tumor site. Effective TTFields treatment planning is expected to improve patient outcomes. Legal entity responsible for the study: Novocure. Funding: Novocure. Disclosure: N. Urman: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. Z. Bomzon: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. H.S. Hershkovich: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. E.D. Kirson: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. A. Naveh: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. R. Shamir: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. E. Fedorov: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. C. Wenger: Full / Parttime employment: Novocure; Shareholder / Stockholder / Stock options: Novocure. U. Weinberg: Full / Part-time employment: Novocure; Shareholder / Stockholder / Stock options: Novocure.
1977TiP
The Australian Exceptional Responders Program: A national collaboration
M. Barnet1, S. Pathmanandavel1, L. McCarthy2, C. Goodnow3, A. Joshua1 Medical Oncology Department, The Kinghorn Cancer Centre, Darlinghurst, Australia, 2 Clinical Trials, St Vincent’s Hospital Sydney, Darlinghurst, Australia, 3Immunogenomics, The Garvan Institute of Medical Research, Darlinghurst, Australia,
1
Background: Analysis of outliers leads to breakthroughs in oncology. Examples of this include pan-approval for anti-PD1 therapy in mismatch repair deficient tumours and
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz268.100/5577207 by guest on 24 October 2019
Pe˛czkowicz-Szyszka: Full / Part-time employment: OncoArendi Therapeutics SA. P. Wolska: Full / Part-time employment: OncoArendi Therapeutics SA. P.S. Sta nczak: Full / Part-time employment: OncoArendi Therapeutics SA. M. Welzer: Full / Part-time employment: OncoArendi Therapeutics SA. E. Nikolaev: Full / Part-time employment: OncoArendi Therapeutics SA. A.M. Siwi nska: Full / Part-time employment: OncoArendi Therapeutics SA. R. Błaszczyk: Full / Part-time employment: OncoArendi Therapeutics SA. B. Borek: Full / Part-time employment: OncoArendi Therapeutics SA. M. Dzie˛gielewski: Full / Part-time employment: OncoArendi Therapeutics SA. A. Gzik: Full / Parttime employment: OncoArendi Therapeutics SA. J. Nowicka: Full / Part-time employment: OncoArendi Therapeutics SA. J. Brzezi nska: Full / Part-time employment: OncoArendi Therapeutics SA. K. Je˛drzejczak: Full / Part-time employment: OncoArendi Therapeutics SA. J. Chrzanowski: Full / Part-time employment: OncoArendi Therapeutics SA. A. Gołe˛biowski: Leadership role, Full / Parttime employment: OncoArendi Therapeutics SA. J. Olczak: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. P. Dobrza nski: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. All other authors have declared no conflicts of interest.
Annals of Oncology