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RENATO V. LA ROCCA, MD, FACP CANCER MEDICINE, NEURO ONCOLOGY NORTON CANCER INSTITUTE LOUISVILLE, KENTUCKY Renato V. La Rocca, MD, FACP Advisory Boards 2014 -2016 Genentech MGI Pharma/Eisai Sanofi Aventis Novocure Celgene Arbor Pharmaceuticals Speakers Bureaus 2014-2016 Merck MGI Pharma/Eisai Sanofi Aventis Celgene 38% of adult brain tumors 80% of malignant brain tumors (~15,000 incident cases/year in the USA) 6.5 new cases/100,000 persons annually in the US 10th leading cause of cancer death overall in the US tumors rarely metastasize but are locally invasive and associated with significant morbidity. Prostate 1 in 6 Lung & bronchus 1 in 13 Colon & rectum 1 in 19 Urinary bladder 1 in 26 Non-Hodgkin lymphoma 1 in 48 Melanoma 1 in 35 Leukemia 1 in 63 Stomach 1 in 92 Brain 1 in 151 Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.6.1 Statistical Research and Applications Branch, NCI, 2012. http://srab.cancer.gov/devcan Incidence Rates by State 2008-2012 Brain and ONS 5 Established • Older age • Male gender • Caucasian race • Higher SES • Genetic syndromes • Family history • Genetic susceptibility • Ionizing irradiation *one or more epidemiologic studies Proposed (partial list)* • Body weight / stature • Handedness • Allergic conditions • Head trauma • Dental x-rays • Cell phone use • Pesticides/ farming • Diet (nitrosamines) • Smoking/ alcohol Study of 1433 intra-cranial meningioma cases, diagnosed between May 1, 2006 and April 28, 2011 compared to 1350 controls matched by age, sex and geography. Increased risk of meningioma is associated with Panorex films taken at a young age or on a yearly or greater frequency with persons reporting receiving such films under the age of 10 years at 4.9 times (95%CI: 1.8-13.2) increased risk of meningioma. EB Claus, et al. Cancer. 2012 Sep 15; 118(18): 4530–4537. Glioblastoma Multiforme Glioblastoma •Invasive •Hypoxic •Phenotypically heterogeneous •Resistant to therapy Courtesy of M. Prados, MD Glioblastoma – An infiltrative Tumor Courtesy of M. Prados, MD Ratio of tumor cells to total cells 1:1 Percentage of tumor Cell population 92% 1:10 6% 1:100 1.8% 1:1000 0.2% Adapted from Wilson CB. Clin Neurosurg. 1992;38:32. Current Therapies STUPP Regimen Antiangiogenesis Agents (Bevacizumab) Novocure TTF Novel Therapies Vaccines CDX -110 (Rindopepimut) ICT-107 Immunotherapy Nivolumab Current Therapies STUPP Regimen Antiangiogenesis Agents (Bevacizumab) Novocure TTF Novel Therapies Vaccines CDX -110 (Rindopepimut) ICT-107 Immunotherapy Nivolumab From August 2000 until March 2002, 573 patients from 85 institutions in 15 countries were randomly assigned to receive radiotherapy (286 patients) or radiotherapy plus temozolomide (287 patients). Focal RT 6 weeks to tumor volume + 2-3 cm margin Stupp, Roger, et al. N Engl J Med 2005; 352:987-996 Current Therapies- STUPP Regimen At a median follow-up of 28 months, 480 patients (84 percent) had died. The median survival benefit was 2.5 months; the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. These data indicate a 37 percent relative reduction in the risk of death for patients treated with radiotherapy plus temozolomide, as compared with those who received radiotherapy alone. Current Therapies- STUPP Regimen MGMT promoter in GBM tissue was analyzed as a predictor of benefits from TMZ treatment. Overall, patients with a silenced MGMT gene had a significantly longer survival. Patients with a methylated MGMT gene had a 2-year survival rate of 22% in those who had received radiation alone and 46% in those who had received radiation and TMZ. Current Therapies STUPP Regimen Antiangiogenesis Agents (Bevacizumab) Novocure TTF Novel Therapies Vaccines CDX -110 (Rindopepimut) ICT-107 Immunotherapy Nivolumab Current Therapies- Antiangiogenic Bevacizumab Microvascular proliferation is a diagnostic hallmark for GBM The vasculature of GBM is both structurally and functionally abnormal: Increased permeability, blood flow and transport properties resulting in vasogenic cerebral edema Increased interstitial pressure and hypoxia The major proangiogenic mediator in GBM is VEGF, which is expressed by infiltrating inflammatory cells, platelets and perhaps most importantly, glioma cells, especially those surrounding zones of necrosis Hypoxia is an important inducer of VEGF expression by glioma cells Chi AS et al. The Oncologist 2009;14:621-636 Current Therapies- Antiangiogenic Bevacizumab Potential Mechanisms of Action of Antiangiogenic Agents Direct anti tumor effect (cancer stem cells, other) Disruption of the angiogenic cascade Potentially decrease vascular leakage resulting in: Decreased peritumoral edema Improved blood flow efficiency, resulting in improved oxygen and drug delivery Inhibition of additional blood vessel formation (for example, through blocking VEGF and decreasing hypoxia) Jain RK. Science 2005;307:58-62 Current Therapies- Antiangiogenic Bevacizumab Bevacizumab: A therapeutic antibody that inhibits VEGF Administered Approved intravenously in the USA for the treatment of : Metastatic colorectal cancer (first-and second-line) Metastatic or locally advanced non-squamous non-small cell lung cancer in combination with carboplatin and paclitaxel Advanced Recurrent renal cell carcinoma glioblastoma as a single agent (May 2009) Bevacizumab Has an impact on progression free survival in the recurrent setting Not proven to be of benefit when given at time of initial diagnosis It allows the patient to be on less steroids (traditionally decadron) which in turn results in less steroid-related toxicities which over the long term, have a significant impact on outcome Bevacizumab Administered intravenously on either a biweekly or once every three week schedule Usually requires a port Potential toxicities: Hypertension Decreased wound healing Proteinuria Fatigue Increased risk of bleeding Increased risk of clotting A Phase 2 Study of Bevacizumab Plus Temozolomide During and After Radiation Therapy for Patients with Newly Diagnosed Glioblastoma Multiforme (GBM) 70 patients with newly diagnosed GBM, compared with a UCLA control cohort who did not receive bevacizumab up front Results: Group that received bevacizumab Progression-free survival: 13.6 months Overall survival: 19.6 months Control Cohort Progression-free survival: 7.6 months Overall survival: 21.1 months Lai et al/ J Clin Oncol 29:142-148, 2010 What agent has efficacy in GBM following progression with Bevacizumab? One hundred patients, aged 36–84 years (median 62 years) with recurrent glioblastoma (GBM), were treated previously with surgery, concurrent radiotherapy and temozolomide and postradiotherapy temozolomide followed by single-agent bevacizumab (BEV) at either first (60 patients) or second recurrence (40 patients). Patients were then treated following progression on BEV only with BEV and carboplatin (75 patients), cyclophosphamide (15 patients) or BCNU (ten patients; BEV+). Following 2 months of BEV+, 60 patients (60%) demonstrated progressive disease and discontinued therapy. Forty patients (40%) had neuroradiographic stable disease. Survival ranged from 1 to 12 months (median: 4 months). Median and 6-month progression free survival was 2.5 months and 5%, respectively. Chamberlain M. Expert Review of Neurotherapeutics 2012, 12:929-936 2004 - Yoram Palti et al – documented with cancer cell lines in vitro that alternating electric fields at frequencies between 100 and 300 kHz can: Disrupt the formation of the mitotic spindle during metaphase (tubulin subunits being very polar molecules) Result in dielectrophoretic movement of polar or charged molecules and organelles during anaphase and telophase, thereby disrupting normal cytokinesis and leading to apoptosis Kirson et al. Cancer Res 2004;64:3288-3295 Gutin and Wong ASCO 2012 Noninvasive Application of Alternating Electric Fields (NovoTTF-100A) No systemic toxicity when applied to various animals and in particular, no significant heating, nor effect (at the frequency range of 100-300 kHz) on excitable tissues such as brain, muscle or heart Gutin and Wong ASCO 2012 25 To date, TTF therapy has been shown to: Effectively inhibit cancer cell growth in various cell lines in vitro (with an optimal frequency in the range of 100 and 300 kHz, dependent on cell type and inversely related to cell size – for example – glioma cells – 200 kHz) The antimitotic effect on cell lines was enhanced by sequentially applying more than one field direction to the cells The combination of TTF therapy and chemotherapy appears to have additive (temozolomide), and in some instances synergistic (paclitaxel) effects. Novocure (Haifa, Israel) developed a portable device for use in humans: Initially applied to humans in a small feasibility trial in 2003 Conducted a pilot trial in Switzerland in patients with recurrent GBM: PFS at 6 months of 50% Median OS 14.4 months Most patients developed grade 1-2 contact dermatitis beneath the transducer arrays on the scalp Gutin and Wong ASCO 2012 Kirson ED et al. Proc Natl Acad Sci USA 2007;104:10152-10157 TTFields with TMZ Novocure EF-14 In the intent-to-treat population, patients treated with TTFields plus TMZ showed a statistically significant increase in PFS, the primary endpoint, compared to TMZ alone (median PFS 7.1 months versus 4.0 months) In the per-protocol population, patients treated with TTFields plus TMZ demonstrated a statistically significant increase in OS compared to TMZ alone (median OS 20.5 months versus 15.6 months) JAMA. 2015;314(23):2535-2543. doi:10.1001/jama.2015.16669. Current Therapies STUPP Regimen Antiangiogenesis Agents (Bevacizumab) Novocure TTF Novel Therapies Vaccines CDX -110 (Rindopepimut) ICT-107 Immunotherapy Nivolumab Current Therapies STUPP Regimen Antiangiogenesis Agents (Bevacizumab) Novocure TTF Novel Therapies Vaccines CDX -110 (Rindopepimut) ICT-107 Immunotherapy Nivolumab Background: Epidermal growth factor variant III (EGFRvIII) is a consistent tumor-specific mutation present in 25-30% of newly diagnosed GBMs Occurs most frequently in de novo GBM and rarely in GBMs progressing from lower grade tumors EGFRvIII expression typically occurs in the presence of wild type EGFR overexpression Given that it is not expressed on normal cells, it is an effective target for immunotherapy Babu R and Adamson DC. Core Evidence 2012;7:93-103 Background: EGFVRvIII contains an inframe deletion of 801 base pairs from the extracellular domain resulting in the fusion of two distant portions of the molecule and creating an antigenic junction with a novel glycine residue The mutation encodes an active tyrosine kinase resulting in: a) Enhanced tumorgenicity b) Increased migration c) Augmented chemo- and radiation resistance Sampson et al. Semin Immunol 20:267-275, 2008 Babu R and Adamson DC. Core Evidence 2012;7:93-103 An EGFRvIII-specific 14-mer peptide vaccine coupled to keyhole limpet hemocyanin (KLH) targeting the EGFRvIII fusion junction is efficacious in syngeneic murine models In human phase 2 trials these vaccines can induce potent T- and B-cell immunity and lead to unexpectedly long PFS and overall survival times as compared to historical controls) The vaccines were successful in eliminating tumor cells expressing EGFRvIII without significant toxicity Compound elicits both humeral and cellular immune responses in preclinical and clinical studies However, recurrence was characterized by the development of EGFRvIII negative tumors Sampson et al. Semin Immunol 20:267-275, 2008 Heimberger and Sampson Expert Opin Biol Ther 9:087-1098, 2009 • Tumor-specific oncogene ideally suited for immune targeting • Expressed in 31% of primary glioblastoma, but not in normal tissue • In-frame deletion of exons 2-7 results in constitutively active protein with unique amino acid sequence at the fusion junction • Epitope is in the extracellular domain; accessible to antibodies and highly immunogenic The ReACT study: a randomized, Phase 2 trial of RINTEGA in combination with bevacizumab (Avastin®) in patients with recurrent EGFRvIII-positive glioblastoma. The ReACT study: a randomized, Phase 2 trial of RINTEGA in combination with bevacizumab (Avastin®) in patients with recurrent EGFRvIII-positive glioblastoma. The ReACT study: a randomized, Phase 2 trial of RINTEGA in combination with bevacizumab (Avastin®) in patients with recurrent EGFRvIII-positive glioblastoma. A Phase 3 study called ACT IV was conducted in newly diagnosed EGFRvIII-positive glioblastoma patients. The 745-patient study was a randomized, double-blind, controlled study of RINTEGA plus granulocytemacrophage colony-stimulating factor (GM-CSF) added to standard of care temozolomide. The ACT IV study was discontinued in March 2016 based on the recommendation of the independent Data Safety and Monitoring Board that the study was unlikely to meet its primary overall survival endpoint in patients with minimal residual disease as both the RINTEGA arm and the control arm were performing on par with each other. In the ACT IV study, RINTEGA performed consistently with prior Phase 2 studies but the control arm significantly outperformed expectations (median OS: RINTEGA 20.4 months vs. control 21.1 months). Current Therapies STUPP Regimen Antiangiogenesis Agents (Bevacizumab) Novocure TTF Novel Therapies Vaccines CDX -110 (Rindopepimut) ICT-107 Immunotherapy Nivolumab ICT-107 Vaccine ICT-107 is an autologous vaccine consisting of the patient’s dendritic cells pulsed with 6 synthetic peptide epitopes targeting the GBM tumor and tumor-stem cell associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100 and IL-13Rα2. Targeting multiple antigens increases the probability of effective treatment, by blocking tumor escape mechanisms associated with single antigen targeting. Dendritic cells reprogrammed with the antigen targets train immune system t-cells to recognize the cancer cells and target them for destruction. One advantage is the ability to manufacture large amounts of activated dendritic cells, allowing enough activated dendritic cells via injection to overcome immune suppression of the activated t cells. ICT-107 Phase 1 Trial (Newly diagnosed patients): Results: Median Progression Free Survival – 16.9 months Two year PFS rate – 43.75% Two Year Overall Survival Rate – 80.2% Median Overall Survival – not reached Expression of 4 ICT-107 targeted antigens in the pre-vaccine tumors correlates with improved survival as measured by PFS and OS Immune responders showed a trend towards a better survival Phuphanich S et al. ASCO 2011, abstract 2042 ICT-107 Phase III Trial (Newly diagnosed patients): The phase 3 registrational trial of ICT-107 in patients with newly diagnosed glioblastoma is designed as a randomized, double-blind, placebocontrolled study of a target number of 414 HLA-A2+ subjects. The primary endpoint in the trial is overall survival (OS). Secondary endpoints include progression-free survival (PFS) and safety, as well as overall survival in the two pre-specified MGMT subgroups. First Patient worldwide on this study was treated at Norton Cancer Institute in June of this year. ICT-107 has been granted orphan drug designation in the US and Europe. Current Therapies STUPP Regimen Antiangiogenesis Agents (Bevacizumab) Novocure TTF Novel Therapies Vaccines CDX -110 (Rindopepimut) ICT-107 Immunotherapy Nivolumab The Immune System In order to protect an individual, the immune system: 1. detects the presence of an infection or malignant cells,1 2. carries out effector functions to contain or to eliminate the affected cells,1 3. performs self-regulation to minimize collateral damage to healthy cells in the body,1 and 4. generates immunological memory so that subsequent exposures to the same antigen are dealt with efficiently.1 1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004 46 Absence of lymphatic architecture within the brain It has now been shown that antigens drain into the CSF through Virchow-Robin spaces to cervical and nasal lymph nodes The blood-brain barrier (BBB) – now considered less relevant Lymphocytes have been shown to penetrate the BBB BBB composition varies in different brain regions Microglia, and macrophages can act as effective APCs within the CNS to initiate T-cell responses Babu R and Adamson DC. Core Evidence 2012;7:93-103 GBM cells express and secrete various immunosuppressive factors including: TGF-b (inhibition of T and NK cell cytotoxicity) IL-10 PGE2 Gangliosides (induction of T-cell apoptosis) B7-H1 and CD70 (induction of T-cell apoptosis) CCL2 (attract Treg cells to the GBM microenvironment)) • 2000- Dana Farber scientists publish paper announcing existence of a protein on normal cells called PD-L1. The researchers found it entwines with a T cell co-receptor (PD-1) deterring the T cell from attacking the cell. • 2001- Freeman, et al. discover and publish a surprising finding- PD-L1 appears on many cancer cells. This meant that the cancer cells had hijacked the mechanism from normal cells in order to evade immune system attack. Pharmaceutical companies quickly seized on the finding, developing antibodies that can block PD-1, PD-L1, or PD-L2. http://www.dana-farber.org/Newsroom/Publications/Hope-Blossoms.aspx Three checkpoint inhibitors have received rapid approval from the U.S. Food and Drug Administration for cancer, including ipilimumab (Yervoy®), atezolizumab (Tecentriq®), pembrolizumab (Keytruda®), and nivolumab (Opdivo®). Yervoy Tecentriq PDL-1 antibody Keytruda Opdivo Melanoma Bladder Metastatic Melanoma Metastatic Melanoma *Hepatocellular * Lung Non Small Cell Lung Cancer Non Small Cell Lung Cancer *Lung *Kidney Head and Neck Cancer Renal Cell Carcinoma *CRC *Breast *Renal Classical Hodgkin Lymphoma *Lymphoma *Breast *GBM *Sarcoma *Multiple Myeloma *Bladder and Kidney *Prostate *Lymphoma *CRC/ Esophageal/ Gastric *Urothelial *Ovarian *Lymphoma * Gastric and CRC and Esophageal *Head and Neck *Hepatocellular *Hepatocellular * Not yet approved for this indication, clinical trials currently active Glioblastoma – Novel Therapies- Immunotherapy There is preclinical evidence to support testing checkpoint inhibitors against primary high grade glioma:. Immune checkpoint receptors such as PD-L1/B7-H1/CD274, a transmembrane receptor ligand and negative regulator of T cell signaling, have been reported to be upregulated in gliomas. Currently three trials with Nivolumab in Glioblastoma therapy: NCI trial NRG BN002- Ipilimumab and/or Nivolumab in Combination with Temozolomide Checkmate 498 Trial: Nivolumab + RT vs. TMZ +RT in unmethylated newly diagnosed GBM Checkmate 548 Trial: Nivolumab + TMZ vs. Placebo + TMZ as concomitant therapy with RT in methylated newly diagnosed GBM Jacobs JF, Idema AJ, Bol KF et al. 2009 NeuroOncol; 11 Wilmotte R, Burkhardt K, Kindler V, et al. Neuro Report 2005, 16 STUPP protocol became standard of care in 2005. At the 5 year analysis of the phase III study that started the new treatment regimen for Glioblastoma, the benefits of adjuvant TMZ + RT have had a lasting effect. Treatment Median Survival 5 year RT 12.1 mos 1.9% RT+TMZ 14.6 mos 9.8% RT+TMZ+Bev 19 mos ? RT+TMZ+Bev+? ? ? The Multi-Disciplinary Team Approach: Essential for Optimal Care Neurosurgeon Neuro-Oncologist Optimal Management of the High-Grade Glioma Patient NeuroPathologist Radiation Oncologist The Conquest of Cancer 1. Knowledge of the molecular phenotype of the cancer 2. Knowledge of the pharmacogenomics of the patient 3. Knowledge of the angiogenic profile/status of the cancer 4. Knowledge of the immunocompetence of the patient 5. Understanding of the comorbities of the patient The Conquest of Cancer 1. Knowledge of the molecular footprint of the tumor 1. 2. Susceptibility to one or a combination of targeted therapies Needs to be in real time and with the understanding of possible metastatic site heterogeneity The Conquest of Cancer 2. Knowledge of the pharmacogenomics of the patient 1. 2. Verification that the therapeutic molecule will achieve therapeutic concentrations and will be appropriately metabolized Knowledge of drug/drug interactions during administration of the therapeutic agent The Conquest of Cancer 3. Knowledge of the angiogenic profile/status of the tumors 1. Determine that in fact the appropriate targeted agent, metabolized appropriately, can effectively arrive at its target at every site The Conquest of Cancer 4. Knowledge of the immunocompetence of the patient 1. A perfect vaccine may not work in every patient in light of a different level of immune competency, which in turn can be impact by: 1. 2. Age Exposure to prior immunosuppressive/immune destroying agents The Conquest of Cancer 5. Understanding of the co-morbidities of the patient and integrating that knowledge into the care plan (e.g., the perfect treatment, in the perfect context (pharmocogenomics, etc) that arrives to target (appropriate angiogenic profile), but exacerbates two of the four comorbidities that the patient has, thus not conferring a survival benefit)
