Photocure ASA · OSL:PHO
Photocure ASA — Corporate Update (August 2016)
122 slides from Photocure ASA's corporate update, Aug 25, 2016
Slide 1: Update on the Management of Bladder Cancer: KOL Breakfast
UPDATE ON THE MANAGEMENT OF BLADDER CANCER: KOL BREAKFAST LE PARKER MERIDIEN NEW YORK Thursday 25th August Kjetil Hestdal, MD, President & CEO Erik Dahl, CFO Ambaw Bellete, President & Head of US Cancer Commercial Operations
Slide 2: Agenda
AGENDA • Welcome by Kjetil Hestdal, President & CEO, Photocure ASA • Cancer of the Urinary Bladder – Dr. Gary Steinberg; Bruce & Beth White Family Professor of Surgery & Vice Chairman of Urology & Director Urologic Oncology, University of Chicago • Genomic Landscape of Bladder Cancer – Dr. Yair Lota
Slide 3: Dr. Gary Steinberg
DR. GARY STEINBERG BRUCE & BETH WHITE FAMILY PROFESSOR OF SURGERY & VICE CHAIRMAN OF UROLOGY & DIRECTOR UROLOGIC ONCOLOGY, UNIVERSITY OF CHICAGO
Slide 4: Cancer of the Urinary Bladder
Cancer of the Urinary Bladder Dr. Gary D. Steinberg Director of Urologic Oncology Vice Chairman Section of Urology
Slide 5: Bladder Cancer Natural History & Etiologic Factors
Bladder Cancer Natural History & Etiologic Factors Bladder Cancer Risk Factors for Bladder Epidemiology (US 2016) Cancer • 76,960 new cases • Cigarettes • 16,390 deaths • Occupation: dyes, rubber, textile, diesel, exhaust • Prevalent population > 550,000 patients ‒ Aromatic amines ‒ Nitrates / Nitro
Slide 6: Increased Risk of Bladder Cancer Among Smokers and Ex-Smokers
Increased Risk of Bladder Cancer Among Smokers and Ex-Smokers • Smoking is one of the most important risk factors associated with bladder cancer • Prevention of cigarette smoking would result in 50% fewer men and 23% fewer women with bladder cancer • Current cigarette smokers have approximately 3-fo
Slide 7: Unmet Medical Needs
Unmet Medical Needs Bladder cancer is associated with a high risk of: • Recurrence:2 • Up to 61% at 1 year • Up to 78% at 5 years for NMIBC • Progression to muscle-invasive disease:2 • Up to 17% at 1 year • Up to 45% at 5 years • Common in patients with CIS, which are often difficult to detect3 High
Slide 8: Bladder Cancer Diagnosis and Presentation
Bladder Cancer Diagnosis and Presentation Cancer of the Urinary Bladder 8
Slide 9: Bladder Cancer Segmentation
Bladder Cancer Segmentation Bladder Cancer Muscle Invasive Non-muscle Invasive ~30% ~70% Low-risk Med/High-risk 70-80% 20-30%
Slide 10: Bladder Cancer Staging
Bladder Cancer Staging Prevalence of Bladder Cancer Staging at Diagnosis1,2 Stage at Diagnosis % of Patients Non-muscle 75% invasive Ta 60% T1 30% Tis 10% Muscle invasive 20% Metastatic 5% 1. Sonpavde G. Postgrad Med. 2005;119(3):30-37. 2. Dalbagni G. Nat Clin Pract Urol. 2007;4(5):254-260. AJCC Can
Slide 11: Bladder Cancer Symptoms, Diagnosis, Surveillance & Follow-up
Bladder Cancer Symptoms, Diagnosis, Surveillance & Follow-up Symptoms • Hematuria • Gross, Microscopic, High Risk • Urinary frequency or urgency • Dysuria Suspicion for Recurrence Surveillance Outpatient Operating ≥ T2 Cystectomy Outpatient Setting Room Setting Ta high grade, White light Pre-diagnos
Slide 12: Non-muscle Invasive Bladder Cancer Standard of Care
Non-muscle Invasive Bladder Cancer Standard of Care: Life-long Follow-up9 TURBT + single-dose chemotherapy - (Blue Light Cystoscopy with Cysview – can be utilized in the TURB procedure) Induction BCG or MMC Follow-up including cystoscopy, urine cytology, urinalysis 0 3 6 9 12 15 18 21 24 Months • Af
Slide 13: Bladder Cancer Surveillance
Bladder Cancer Surveillance • Cystoscopy – Sometimes misses High-Grade CIS • 28% increased detection rate using Cysview* • Unable to detect Upper Tract Disease • Urine Cytology – Detects High-Grade CIS – Frequently misses Low-Grade Papillary Tumors – Overall sensitivity 30%, overall Specificity = 95
Slide 14: Urine Cytology
Urine Cytology Cancer of the Urinary Bladder 14
Slide 15: Combining Morphology with DNA Technology: Molecular Cytology
Combining Morphology with DNA Technology: Molecular Cytology Cytology Molecular Cytology Cancer of the Urinary Bladder 15
Slide 16: Imaging
Imaging Cancer of the Urinary Bladder 16
Slide 17: Rationale for Early Detection
Rationale for Early Detection • Good cure rates for non-muscle invasive disease • Treatment of early tumors is relatively less complicated but high cost due to number of diagnostic procedures • Opportunity exists to detect tumors destined to invade muscle before they actually do so Cancer of the Uri
Slide 18: Office Cystoscopy
Office Cystoscopy • Thorough Endoscopy of Urethra and Bladder • Local Anesthesia • Photography of Bladder • Cytology – to assess for Cancer Cells Cancer of the Urinary Bladder 18
Slide 19: Bladder Tumor - Cystoscopy
Bladder Tumor - Cystoscopy Cancer of the Urinary Bladder 19
Slide 20: Blue Light Cystoscopy with Cysview
Blue Light Cystoscopy with Cysview • Diagnostic tool to aid detection of bladder Standard White Light Cystoscopy tumors Mode 1 • Technology – Instill a photosensitizing agent into the bladder via a catheter – The agent induces preferential intracellular accumulation of photoactive porphyrins (PAPs),
Slide 21: TURBT: Diagnostic and Therapeutic
TURBT: Diagnostic and Therapeutic • Establishes pathologic diagnosis, including grade and stage of disease • Also should be viewed as a complete oncologic procedure, especially in low grade non - muscle invasive disease • Repeat TURBT • May upstage from T1 to T2 in up to 40- 50% • Residual disease o
Slide 22: Bladder Cancer Diagnosis: Challenges and Future Directions
Bladder Cancer Diagnosis: Challenges and Future Directions • Molecular markers: Detection, Risk Stratification, Prediction of Response to Treatment – Whole genome sequencing – Epigenetics – miRNA microarrays DNA Methylation marker associated with progression and recurrence Comparison of Mutation Fre
Slide 23: Non-Muscle Invasive Disease
Non-Muscle Invasive Disease • TURBT • Chemotherapy / Immunotherapy • Detection / Surveillance • Watchful Waiting Cancer of the Urinary Bladder 23
Slide 24: NMIBC: Evaluation / Treatment
NMIBC: Evaluation / Treatment Hematuria CT Scan, Cystoscopy, Cytology TURBT large, multiple tumors, high grade small non-invasive tumor, low grade 4-6 wks Repeat TURBT 3 months Upstaged Negative or Surveillance – Cystoscopy same stage, grade Cytology FISH 3-4 wks 6 weeks BCG 6 wks Cystoscopy / Bladd
Slide 25: NMIBC: Current Challenges
NMIBC: Current Challenges • Urinary markers to replace cystoscopy • 2nd line therapies for BCG-failure – Intravesical – When to proceed to cystectomy • Biomarkers of disease aggressiveness – predicting progression and recurrence – NMIBC – 60-80% chance of recurrence at 5 years with surgery alone – E
Slide 26: BCG: Mechanism of Action
BCG: Mechanism of Action Redelman-Sidi et al. The mechanism of action of BCG therapy for bladder cancer—a current perspective. Nat. Rev. Urol. 11, 153–162 (2014). Cancer of the Urinary Bladder 26
Slide 27: Biomarkers to Predict Response to BCG?
Biomarkers to Predict Response to BCG? •glutathione S-transferase theta 1 (GSTT1) –Genomic polymorphisms may predict response –GSTT1-positive up to 14-fold higher risk of early BCG failure •Urinary cytokine panel – CyPRIT –9 inducible cytokines in urine –Predict recurrence with 85.5% accuracy *Kang
Slide 28: Cancer Immunotherapy
Cancer Immunotherapy Recognition of cancer cells by T cells Normally -- upregulation of immune checkpoint receptors • Redelman-Sidi et al. The mechanism of action of BCG therapy for bladder cancer—a current perspective. Nat. Rev. Carosella ED. Eur Urol 68 (2015): 267-279 Cancer of the Urinary Bladde
Slide 29: Cancer Immunotherapy
Cancer Immunotherapy Tumors can escape response by direct or indirect (APC) inhibition of various immune checkpoint proteins Cancer of the Urinary Bladder 29
Slide 30: Therapeutic Targets
Therapeutic Targets Chen ED. Immunity 68 (2013): 267-279 Cancer of the Urinary Bladder 30
Slide 31: Current Clinical Trials
Current Clinical Trials Lerner, Seth P., et al. “Summary and Recommendations from the National Cancer Institute’s Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer.” Bladder Cancer 2, no. 2. Cancer of the Urinary Bladder 31
Slide 32: Current Clinical Trials (continued)
… Lerner, Seth P., et al. “Summary and Recommendations from the National Cancer Institute’s Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer.” Bladder Cancer 2, no. 2. Cancer of the Urinary Bladder 32
Slide 33: Invasive Bladder Cancer
Invasive Bladder Cancer • Lethal disease if not treated appropriately • Surgery remains cornerstone therapy Cystoscopic view of papillary bladder cancer Cancer of the Urinary Bladder 33
Slide 34: Muscle Invasive Disease
Muscle Invasive Disease • Radical Cystectomy • Lymph Node Dissection • Chemotherapy Cancer of the Urinary Bladder 34
Slide 35: Radical Cystectomy
Radical Cystectomy Cancer of the Urinary Bladder 35
Slide 36: Treatment of Invasive Bladder Cancer: Bladder Preservation
Treatment of Invasive Bladder Cancer: Bladder Preservation • TURBT • Chemotherapy • Radiation Therapy Cancer of the Urinary Bladder 36
Slide 37: Treatment of Invasive Bladder Cancer: Bladder Preservation
Treatment of Invasive Bladder Cancer: Bladder Preservation TURBT Induction therapy MCV XRT + concurrent cisplatin urologic evaluation incomplete response complete response Consolidation therapy recommend radical MCV cystectomy XRT TURBT: Transurethral resection of bladder tumor, MCV: Methotrexate, C
Slide 38: Future Directions: The Cancer Genome Atlas Project
Future Directions: The Cancer Genome Atlas Project • 2014: First 131 patients sequences –Somatic mutation, DNA copy number variants, mRNA and microRNA expression, protein expression, DNA methylation –One of the highest somatic mutation rates across cancers –32 significantly mutated genes involved wi
Slide 39: Future Directions: The Cancer Genome Atlas Project
Future Directions: The Cancer Genome Atlas Project Large opportunity for translational research & Targeted Therapy The Cancer Genome Atlas Research Network Nature 507, 315-322 (2014) doi:10.1038/nature12965 Cancer of the Urinary Bladder 39
Slide 40: Take Home Points
Take Home Points •Bladder carcinoma is a common and deadly cancer usually diagnosed in the elderly and costs $4 billion per year in the US •Non-muscle invasive disease requires resection and often intravesical therapy with close follow up •Gold standard treatment for muscle invasive disease remains
Slide 41: Dr. Yair Lotan
DR. YAIR LOTAN PROFESSOR, CHIEF UROLOGIC ONCOLOGY, HOLDER OF THE HELEN J. & ROBERT STRAUSS PROFESSORSHIP, UNIV. OF TEXAS SOUTHWESTERN MEDICAL CENTER
Slide 42: Genomic Landscape of Bladder Cancer
Genomic Landscape of Bladder Cancer Yair Lotan Professor of Urology
Slide 43: Acknowledgement
Acknowledgement • Seth Lerner, BCM • Shahrokh Shariat, Univ. of Vienna • William Kim, UNC
Slide 44: Disclosures
Disclosures • Research Studies: – Abbott – Cepheid – Genomedx – Pacific Edge – MDxHealth – Photocure
Slide 45: Outline
Outline • Background • State of genomics • Potential Applications • Future directions
Slide 46: Bladder Cancer: Epidemiologic Features
BLADDER CANCER: Epidemiologic Features USA in 2015: 74,690 new cases 553,496 prevalence 15,580 deaths Europe in 2012: 118,280 new cases >600,000 prevalence >20,000 deaths • 4th most common in ♂ and 11th in ♀ • Women with BCa Peak incidence: after have worse 7th decade (20%mortality >80) than man!
Slide 47: Likelihood of Tumor Progression
Likelihood of Tumor Progression
Slide 48: Progression-free Survival Probability
Recurrence after Radical Cystectomy 100 90 Pa n=19 Progression-free Survival Probability 80 Pis n=51 70 P1 n=113 60 P2 n=275 50 P3 n=245 40 5 yr. ± SE 10 yr. ± SE 30 Pis 75.3 ±9.4% 75.3 ±9.4% P4 n=96 Pa 88.8 ±7.5% 88.8 ±7.5% 20 P1 80.8 ±4.5% 71.4 ±6.5% P2 71.6 ±3.2% 63.3 ±4.9% 10 P3 44.2 ±3.9% 38.6
Slide 49: US Drug Approvals in GU Cancers
US Drug Approvals in GU Cancers Valrubicin Atezolizumab 2016 Galsky et al, Clinical Advances in Hematology & Oncology, 2013
Slide 50: Comprehensive molecular characterization of urothelial bladder carcinoma
ARTICLE OPEN doi:10.1038/nature12965 Comprehensive molecular characterization of urothelial bladder carcinoma The Cancer Genome Atlas Research Network* Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths pet wide. So far, no molecularly targeted agents
Slide 51: Three clusters - mutation/copy number data
Three clusters - mutation/copy number data • Mean mutation rate per tumor 7.7!!!! • No unique mutation for all cancers • Not Prostate Cancer
Slide 52: Subtypes of High Grade Bladder Cancer
Subtypes of High Grade Bladder Cancer • High grade tumors segregate into clusters • Differences in genetics drive: – Prognosis Umbrella cells • Basal cell worse – Response to therapy – Gender • Basal resemble breast • More common women Basal cells – Immune response (Castillo-Martin 2010)
Slide 53: How Do We Use Genomic Information?
How Do We Use Genomic Information? • Diagnosis – Urine markers • Prediction of Outcomes – Tissue markers • Predict Response to Therapy • Identify Novel Therapeutics
Slide 54: Improved Bladder Cancer Detection
Improved Bladder Cancer Detection
Slide 55: Current Diagnosis/Surveillance of Bladder Cancer
Current Diagnosis/Surveillance of Bladder Cancer • Visual inspection of bladder (Cystoscopy) and pathologic inspection of urine (Cytology) • Cystoscopy Limitations – Miss lesions especially carcinoma in situ – Can’t see upper tract disease – Invasive • Cytology is inconsistent – Misses 20% of HG dis
Slide 56: Tumor Marker Approaches
Tumor Marker Approaches • Biochemical detection of proteins or other urinary compounds – NMP22 • Detection of cellular antigen by immunohistochemistry or cytochemistry – ImmunoCytTM • Detection of genetic alterations – FISH
Slide 57: NMP22 BladderChek Test
NMP22 BladderChek Test • Detects elevated amounts of the nuclear matrix protein • Point-of-care test • FDA-approved for diagnosis of bladder cancer in high-risk patients.
Slide 58: UroVysion
UroVysion • Detects aneuploidy via Fluorescence in situ Hybridization • Abnormal result – More than 2-4 cells with multiple chromosomal gains – More than 9-11 cells with loss of both copies of 9p21 Normal (p16 gene) Positive
Slide 59: ImmunoCyt/uCyt+
ImmunoCyt™/uCyt+™ • Uses antibodies labeled with fluorescent markers – a mucin glycoprotein – carcinoembryonic antigen (CEA) • Any cells expressing tumor antigen are then detected by fluorescence microscopy. • Recommended in combo with cytology
Slide 60: Cxbladder Monitor
Cxbladder Monitor • Measures the gene expression levels of five biomarkers and incorporates previous UC occurrence to represent a bladder cancer signature used to: – MDK: Cell proliferation, migration, and angiogenesis in cancer cells – HOXA13: Cell differentiation and the morphogenesis and differen
Slide 61: Urinary Markers – selection of appropriate markers
Urinary Markers – selection of appropriate markers according to clinical needs • No single marker has demonstrated superior clinical utility over cytology and cystoscopy – All test sensitivities > cytology (low grade!) – All test specificities < cytology • There is no “ideal” marker • Not Recommende
Slide 62: Improved Prediction of Outcomes
Improved Prediction of Outcomes
Slide 63: Many Pathways result in Cancer development and Spread
Survivin Many Pathways result in Cancer development and Spread MVD Mitra et al., 2011
Slide 64: Using Tissue Markers to Predict Outcomes after Cystectomy
Using Tissue Markers to Predict Outcomes after Cystectomy MORE ALTERATIONS= WORSE OUTCOMES Combined cell-cycle biomarkers Combined apoptosis biomarkers Shariat et al., J Clin Oncol 2003 Karam et al., Lancet Oncol 2007
Slide 65: Understanding the Biology of Cancer Improves Prediction
0 10 20 30 40 50 60 70 80 90 100 Prediction of disease recurrence in 191 Points Age at surgery 30 40 50 60 70 80 90 2 P. Grade 3 1 Lymphova 0 1 3 No. of Markers 0 2 4 Total Points 0 20 40 60 80 100 120 140 160 180 patients with pT1-T3 N0 M0 1(Y)REC-Free.Surv. 0.995 0.99 0.98 0.97 0.95 0.93 0.9 0.86
Slide 66: Genomic Classifiers Will Likely Be Commercially Available Soon
Performance of individual clinicopathologic variables and classifiers in the validation set for predicting cancer recurrence. GENOMIC CLASSIFIERS WILL LIKELY BE COMMERCIALLY AVAILABLE SOON Anirban P. Mitra et al. JNCI J Natl Cancer Inst 2014;106:dju290 © The Author 2014. Published by Oxford Universi
Slide 67: Predict Response to Therapy
Predict Response to Therapy
Slide 68: Progression-free Survival Probability
Recurrence after Radical Cystectomy 100 90 Pa n=19 Progression-free Survival Probability 80 Pis n=51 70 P1 n=113 60 P2 n=275 50 P3 n=245 40 5 yr. ± SE 10 yr. ± SE 30 Pis 75.3 ±9.4% 75.3 ±9.4% P4 n=96 Pa 88.8 ±7.5% 88.8 ±7.5% 20 P1 80.8 ±4.5% 71.4 ±6.5% P2 71.6 ±3.2% 63.3 ±4.9% 10 P3 44.2 ±3.9% 38.6
Slide 69: SWOG 8710 Randomized Neoadjuvant MVAC Chemotherapy Trial
SWOG 8710 Randomized Neoadjuvant MVAC Chemotherapy Trial Grossman et al., NEJM 2003
Slide 70: Dilemma of Neo-adjuvant Chemotherapy
Dilemma of Neo-adjuvant Chemotherapy • Level 1 evidence shows improvement in survival • 6% ↑ in 5yr survival only 20-25% of unselected pts benefit • Not everyone seems to need NAC – Organ-confined BC (~50% in contemporary series) have excellent survival following RC alone (80% cure) – NAC favors a
Slide 71: The COXEN Principle: Prediction of treatment outcome
The COXEN Principle: Prediction of treatment outcome (Theodorescu et. al, Proc Natl Acad Sci U S A. 2007;104(32):13086) Downstaging vs. COXEN Score MSKCC & UVA NCI-60 Panel COXEN Score 2 3 1 2 3 1 575A Sensitiv 1 3 2 1 1 3 2 3 2 Methotrexate Vinblastine Doxorubicin Cisplatin COXEN NO Downstage Downs
Slide 72: SWOG 1314: COXEN with Neoadjuvant Chemotherapy
SWOG 1314: A Randomized Phase II Study of COXEN with Neoadjuvant Chemotherapy for Localized Muscle-Invasive Bladder Cancer PI: Thomas Flaig, MD Impact: Transform thinking about patient Purpose: Biomarker validation and Biomarker discovery selection Primary for To study objective: neoadjuvant chemoth
Slide 73: Choi et al., Cancer Cell, 2014
Choi et al., Cancer Cell, 2014
Slide 74: Clinical Validation of Chemotherapy Response Biomarker ERCC2
From: Clinical Validation of Chemotherapy Response Biomarker ERCC2 in Muscle-Invasive Urothelial Bladder Carcinoma JAMA Oncol. Published online June 16, 2016. doi:10.1001/jamaoncol.2016.1056 • ERCC2 is the helicase that unwinds DNA for repair via the nucleotide excision repair pathway • Important fo
Slide 75: Summary
Summary • Need to improve selection of patients for multi-modal therapy • Cooperative group trial on COXEN will provide important information but not for years • Understanding biology using genomics is best chance to select patients
Slide 76: Identify Novel Therapeutics
Identify Novel Therapeutics
Slide 77: How can TCGA Inform Clinical Questions
How can TCGA Inform Clinical Questions • 69% of tumors harbor potential therapeutic targets – PI3K/AKT/mTOR (42%) – RTK/MAPK (44%) – Chromatin regulatory genes – Novel biomarkers/targets – STAG2? • Should cancer treatment be organ specific or target/pathway specific? • Molecular classifier
Slide 78: Majority of samples have cell cycle regulatory pathways altered
Majority of samples have cell cycle regulatory pathways altered Left box: mutation Right box: copy number Red: activated or amplified Blue: inactivated or deleted MDM2 CDK4/6 inhibitors: inhibitors: RG-7112 Palbociclib RO5503781 LEE001 DS-3032b LY2835219 CGM097 MK-8242 SAR405838
Slide 79: Reverse translation from clinic to lab
Reverse translation from clinic to lab E.g. Everolimus (mTORC1 inhibitor) in relapsed bladder cancer Negative trial: 1 CR+1PR in 45 patients Pt. with CR remained NED on drug for 36 mos Milowsky et al., BJUI 2013 MSKCC lab: whole genomic sequencing identified 2 gene mutations in this patient:
Slide 80: RTK/Ras/PI3K pathways: HER2/ERBB2 Activation
RTK/Ras/PI3K pathways HER2/ERBB2 Activation as a potential therapeutic target Trastuzumab Trastuzumab-DM1 Lapatinib [NCT00447226] Neratinib [NCT01953926] DN24-02 [NCT01353222] Her2 – CAR (CAGT/BCM) Her2 levels comparable to Her2+ breast cancer
Slide 81: NCI MATCH Molecular Analysis for Therapy Choice
NCI MATCH Molecular Analysis for Therapy Choice Precision medicine working group • Precision medicine clinical trial • Genotype to phenotype • Led by ECOG-ACRIN with NCI • Multiple (up to 30) Phase II arms • Eligibility based on molecular characteristics Natl Academy of Sciences 2011
Slide 82: Genes rarely mutated in one tumor type occur frequently across types
Genes that are rarely mutated in one tumor type occur frequently across tumor types • Alterations in MTOR may also predict sensitivity to everolimus [Wagle et al. Cancer Discovery 2014] • Low frequency alterations in aggregate and across pathways are even more powerful. Courtesy Ali Amin-Mansour Bro
Slide 83: Avoiding the PD-1 Immunocheckpoint Pathway
Avoiding the PD-1 Immuncheckpoint Pathway1 Priming Phase Effector Phase Activation dendritic cell naive T-cell Activated T-cell Tumor cell • PD-1 is expressed more PD-1 - on activated T-cells during the effector phase of the immune response Antigen TCR MHC • PD-L1 and PD-L2 turn off the T-cell activ
Slide 84: Atezolizumab in locally advanced and metastatic urothelial carcinoma
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial The PD-L1 tumour-infiltrating immune cell (IC) status was defined by the percentage of PD-L1-positive
Slide 85: Summary
Summary • Delineation of the genomic landscape and molecular subtypes will accelerate biomarker and drug development • NCI leading in design and support for “basket-type” clinical trials for Phase I/II
Slide 86: Molecularly-Driven Diagnostic & Therapeutic Development
Molecularly-Driven Diagnostic & Therapeutic Development • Therapies will increasingly target the key molecular hubs that drive cancer growth - not just individual mutations • Treatments more personalized taking into account – when and how to intervene to hit the right targets – how treatments are li
Slide 87: Flexible clinical research guided by biomarkers
Flexible clinical research guided by biomarkers • Criteria for entry in a trial based on molecular characteristics Inclusion only of the participants most likely to respond based on molecular characteristics Faster & more conclusively answers • Need to screen larger numbers of pts to identify pa
Slide 88: Genomic Based Trial Design Key Hurdles
Genomic Based Trial Design Key Hurdles • Biomarker validity • Next-Gen sequencing CLIA approved lab • Regulatory/FDA • Pharma/Biotech support • Funding • Trial leadership • Target/pathway prioritization
Slide 89: Dr. James McKiernan
DR. JAMES MCKIERNAN JOHN K. LATTIMER PROFESSOR & CHAIRMAN DEPT. OF UROLOGY, COLLEGE OF SURGEONS & UROLOGIST-IN-CHIEF AT NY PRESBYTERIAN COLUMBIA HOSPITAL & VICE CHAIR, AUA GUIDELINES COMMITTEE
Slide 90: Risk Stratification and Guidelines for Management of NMIBC
Risk Stratification and Guidelines for Management of NMIBC James McKiernan M.D. John K. Lattimer Professor and Chair Department of Urology Columbia University
Slide 91: A case study
Guidelines in NMIBC 2016 A case study • 57 year-old-male executive with first ever TURBT with white light • Reveals HG T1 UCC with squamous variant histology no muscle in the specimen no perioperative chemo • Waits 5 weeks and begins BCG therapy • Receives antibiotics with each BCG infusion • Does n
Slide 92: Guidelines in NMIBC
Guidelines in NMIBC • Levels of evidence and strength of recommendation • Risk Stratification CUETO, EAU, WHO 1973 vs 2004 • Initial evaluation • TURBT and re-TURBT • Intravesical therapy • Enhanced cystoscopy • Surveillance schedules
Slide 93: Epidemiology
EPIDEMIOLOGY NMIBC represents approximately 75% of the 74,000 estimated new bladder cancer cases diagnosed in the United States in 2015. Bladder cancer is more common in males than females with a ratio of approximately 3:1, and it is the fourth most common solid malignancy in men. Siegel 2015
Slide 94: Presentation & Diagnosis
PRESENTATION & DIAGNOSIS The most common presenting symptom is painless hematuria • Urinary cytology • Bimanual exam • Imaging • CT • MRI A diagnosis of bladder cancer is confirmed by direct visualization of the tumor using cystoscopy and TURBT. An adequate TURBT requires complete resection of all v
Slide 95: Staging & Grading
STAGING & GRADING Staging of primary tumors (T) in bladder cancer TX Primary tumor cannot be assessed Staging for bladder cancer is Ta Noninvasive papillary carcinoma separated into clinical and Tis Carcinoma in situ (CIS) pathologic stage, as outlined by the T1 Tumor invades lamina propria American
Slide 96: Staging & Grading
STAGING & GRADING 2004 World Health Organization/ International Society of Urologic Grade important Pathologists: Classification of Non-muscle Invasive Urothelial Neoplasia prognostic factor for Hyperplasia (flat and papillary) recurrence and Reactive atypia progression Atypia of unknown significanc
Slide 97: Prognosis
PROGNOSIS The survival prognosis for patients with NMIBC is relatively favorable, with the cancer-specific survival (CSS) in high-grade disease ranging from approximately 70-85% at 10 years and a much higher rate for low-grade disease. The rates of recurrence and progression to MIBC Risk of Risk of
Slide 98: Levels of Evidence
Levels of Evidence • 1 - Evidence from meta-analysis or randomized trial o Should or will (Standard) • 2 - Evidence from a controlled study without randomization or from well-designed quasi-experimental study o May consider • 3 - Evidence from comparative studies, correlation studies and case report
Slide 99: AUA Risk Stratification System
AUA RISK STRATIFICATION SYSTEM Low Risk Intermediate Risk High Risk LGa solitary Ta ≤ 3cm Recurrence within 1 year, HG T1 LG Ta PUNLMPb Solitary LG Ta > 3cm Any recurrent, HG Ta LG Ta, multifocal HG Ta, >3cm (or multifocal) HGc Ta, ≤ 3cm Any CISd LG T1 Any BCG failure in HG patient Any variant histo
Slide 100: Guideline: Risk Stratification
GUIDELINE: RISK STRATIFICATION 5. At the time of each occurrence/recurrence, a clinician should assign a clinical stage and classify a patient accordingly as “low-,” “intermediate-,” or “high-risk.” (Moderate Recommendation; Evidence Strength: Grade C) EORTC/CUETO Model Tumor size, tumor focality,
Slide 101: Guideline: TURBT/Repeat Resection
GUIDELINE: TURBT/REPEAT RESECTION 12. In a patient with non-muscle invasive disease who underwent an incomplete initial resection (not all visible tumor treated), a clinician should perform repeat transurethral resection or endoscopic treatment of all remaining tumor if technically feasible. (Strong
Slide 102: Routine Re-TUR
Routine Re-TUR Can it make BCG better? • 1,021 patients treated with BCG at MSKCC • Viable disease found in 55% • 44% relapse if no re -TUR and 9% if re-TUR • Only significant predictor of 5 -yr cure was re-TUR!! Sfakianos and Herr J Urol 2013
Slide 103: Guideline: Intravesical Therapy
GUIDELINE: INTRAVESICAL THERAPY 15. In a patient with suspected or known low- or intermediate-risk bladder cancer, a clinician should consider administration of a single postoperative instillation of intravesical chemotherapy (e.g., mitomycin C or epirubicin) within 24 hours of TURBT. In a patient w
Slide 104: Guideline: Intravesical Therapy
GUIDELINE: INTRAVESICAL THERAPY 16.In a low-risk patient, a clinician should not administer induction intravesical therapy. (Moderate Recommendation; Strength of Evidence Grade C) 17.In an intermediate-risk patient a clinician should consider administration of a six week course of induction intraves
Slide 105: Guideline: Intravesical Therapy
GUIDELINE: INTRAVESICAL THERAPY 19.In an intermediate-risk patient who completely responds to an induction course of intravesical chemotherapy, a clinician may utilize maintenance therapy. (Conditional Recommendation; Evidence Strength: Grade C) 20.In an intermediate-risk patient who completely resp
Slide 106: Guideline: Enhanced Cystoscopy
GUIDELINE: ENHANCED CYSTOSCOPY 30. In a patient with NMIBC, a clinician should offer blue light cystoscopy at the time of TURBT, if available, to increase detection and decrease recurrence. (Moderate Recommendation; Evidence Strength: Grade B) 31. In a patient with NMIBC, a clinician may consider us
Slide 107: Enhanced Cystoscopy: Revealing the Unseen Enemy
Enhanced Cystoscopy Revealing the Unseen Enemy
Slide 108: Blue Light Cystoscopy with Cysview: Meta-analysis Results
Blue Light Cystoscopy with Cysview Results from meta-analysis in 9 studies and > 2000 patients At least one additional Ta/T1 was found in 24.5% of 26.7% of the CIS patients were diagnosed with the patients p<0.001 BLCC only p<0.001 Burger M et al., European Journal of Urology 2013
Slide 109: Blue Light Cystoscopy with Cysview impacts recurrence
Blue Light Cystoscopy with Cysview impacts recurrence of bladder cancer Rate of recurrence reduced1 Time to recurrence prolonged2 Rate of recurrence is reduced by 10.9% p= <0.006 2. Grossman et al: Journal of Urology 2012 1. Burger et al: European Journal of Urology 2013
Slide 110: Blue light cystoscopy with Cysview impacts progression
Blue light cystoscopy with Cysview impacts progression of bladder cancer Rate of progression reduced1 Time to progression prolonged2 Meta analysis in 5 studies and 1301 patients: • BLCC: 44/644 patients (6.8%) • WLC: 70/650 patients (10.7%), p=0.01 p=0.05 “This meta-analysis supports the assumption
Slide 111: EAU Guidelines 2013 Enhanced Cystoscopy
EAU Guidelines 2013 Enhanced Cystoscopy • If equipment is available, use fluorescence -guided (PDD) biopsy instead of random biopsies when bladder CIS or HG tumor is suspected (e.g., positive cytology, recurrent tumor with previous history of a HG lesion).
Slide 112: Guideline: Surveillance & Follow Up
GUIDELINE: SURVEILLANCE & FOLLOW UP 32.After completion of the initial evaluation and treatment of a patient with NMIBC, a clinician should perform the first surveillance cystoscopy within three to four months. (Expert Opinion) 33.For a low-risk patient whose first surveillance cystoscopy is negativ
Slide 113: EAU Guidelines 2013 Surveillance
EAU Guidelines 2013 Surveillance • Low-risk Ta cysto at 3 months. If negative, subsequent cysto 9 months later, then yearly for 5 years. • High-risk cysto and urinary cytology every 3 months for 2 years, every 6 months until 5 years, then yearly. • Intermediate-risk Ta in-between follow-up scheme us
Slide 114: EAU Guidelines 2013 Surveillance
EAU Guidelines 2013 Surveillance • Yearly upper tract imaging for high-risk tumors. • After BCG for CIS consider R-biopsies or biopsies with PDD at 3 or 6 months. • Positive cytology and no visible tumor in the bladder, R-biopsies or biopsies with PDD (if equipment is available) and CT urography, pr
Slide 115: Summary
Summary • NMIBC heterogenous and dangerous disease • Although complex guidelines and risk groupings aid in decision making • All decisions are based upon stage and grade of tumor as well as interaction with prior treatments • Thorough cystoscopic exam and complete TURBT are the cornerstone of all de
Slide 116: NMIBC Research Team 2015-2016
Columbia/NYPH NMIBC Research Team 2015-2016 Ifeanyi Onyeji Justin Matulay MD Wilson Sui Solomon Woldu MD Maxwell James Lamont Barlow MD Christopher Haas Alan Nieder MD Alex Bandin Arindem Roychoudry PhD Jamie Pak Cathy Mendelsohn PhD Michael Shen PhD Sara Barrone MA Christopher Anderson MD, MPH Joel
Slide 117: Company Update
COMPANY UPDATE Kjetil Hestdal, MD, President & CEO
Slide 118: Disclaimer
DISCLAIMER The information included in this Presentation contains certain forward-looking statements that address activities, events or developments that Photocure ASA (“the Company”) expects, projects, believes or anticipates will or may occur in the future. These statements are based on various as
Slide 119: Hexvix / Cysview: Current Status in US and EU
HEXVIX / CYSVIEW: CURRENT STATUS IN US AND EU • Hexvix® (EU) / Cysview ® (US) first approved drug-device procedure for improved detection and management of bladder cancer • Commercialized by Photocure in US and Nordic regions – Strategic partners in other regions • LTM in market sales growth of 18%
Slide 120: Hexvix / Cysview: Expanding into the Surveillance Segment
HEXVIX / CYSVIEW: EXPANDING INTO THE SURVEILLANCE SEGMENT • Surveillance following initial diagnosis represents a significant growth opportunity – Utilizes flexible cystoscope – Market potentially 2 -3 times as large as TURB • Secured alignment with FDA on study design necessary to obtain label exte
Slide 121: Photocure Summary
PHOTOCURE SUMMARY • Driven by Hexvix / Cysview for detection and management of bladder cancer Profitable Commercial Franchise – NOK 230 M ($ ~30M) global in market sales LTM • Strong position in US and local market Established own sales operations • Potential to expand urology portfolio to leverage
Slide 122: Q&A
Q&A PHOTOCURE®