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Tumour Agnostic Treatments
This document summarizes the story of Ted Taylor, a glioblastoma patient who was given a terminal diagnosis but found an effective targeted therapy called Vitrakvi after extensive research. Vitrakvi targets NTRK fusions and Ted tested positive for this biomarker. He worked with his oncologists to gain access to Vitrakvi from Canada and the US. While on Vitrakvi, Ted has experienced significant tumor shrinkage with minimal side effects compared to standard chemotherapy. He hopes to help other patients advocate for themselves to find effective targeted therapies.
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Tumour Agnostic Treatments
- 1. TRKing the pathto precision oncology; the NTRK story Poul Sorensen, MD, PhD BC Cancer Research Centre Vancouver, BC, Canada
- 2. There is anincreasing shift toward targeted therapy for cancer CONFIDENTIAL 2 Chemotherapy Targeted Therapy • In personalized medicine, clinicians use biomarkers to predict a patient's response to therapy • Patients are more likely to get therapies with the greatest impact with fewer side effects • Anticancer drugs may be highly effective in some, but less effective in others • Patients are exposed to the risk of side effects
- 3. Personalized Oncology (PrecisionOncology) -- incorporating genomic information into treatment decision-making EGFR mutation ALK1 fusion ROS1 fusion Checkpoint inhibitors erlotinib crizotinib Genomic sequencing of lung tumors crizotinib Mutation burden pembrolizumab nivolumab PD-L1 atezolizumab LungCancer Chemotherapy TissueBiopsy Generic pathology based care Liquid biopsy and other specialized pathology techniques osimertinib EGFR resistance mutation
- 4. Histomolecular entity versusmolecular subtypes of a common cancer: the ski resort analogy • Molecular subtypes of common cancer Multiple pathogenetic pathways and treatment options • Histomolecular entity Single pathogenetic pathway and dominant treatment
- 5. Four Major Typesof Genomic Alterations in Cancer Single nucleotide substitutions (including splice sites) Small insertions/deletions* Copy number amplifications Rearrangements/ fusions T T A A C C G T C A A C C G Next round of replication G-C and A-T base pairs deleted Next round of replication A-T base pair added • Activating Mutations in Oncogenes OR Disruptive Mutations in Tumor Suppressors • e.g. NTRK fusions Gene fusions: chimeric genes formed from fusion of coding sequences from two normally separate partner genes
- 6. Discovery of the ETV6-NTRK3gene fusion in pediatric sarcomas
- 7. By microscopy, benignfibromatosis can look identical to malignant congenital fibrosarcoma Fibromatosis Congenital Fibrosarcoma Could we find a cytogenetic or molecular marker to distinguish these two entities?
- 8. t(12;15)(p13;q25) in congenital fibrosarcoma SAM ETV6(chr 12) ETV6-NTRK3 kinase NTRK3 (chr 15) PI3K AKT Bcl-2 cell survival Ras Erk1/2 Cyclin D1 GTP Cell growth and division
- 9. Ectopic expression ofETV6-NTRK3 transforms mouse fibroblasts 1. Changes in cell appearance 2. Ability to grow without attachment to underlying tissues (soft agar colony formation) 3. Cells tumorigenic in nude mice Control ETV6-NTRK3 D. Wai et al, Oncogene 2000 Control ETV6-NTRK3
- 10. Mammary-analogue secretory carcinoma (MASC)of salivary glands Photomicrograph courtesy of Dr. Ken Berean Human secretory breast carcinoma ETV6-NTRK3 is a pathognomonic biomarker in both diseases, despite different histologies and anatomic locations
- 11. Hyperplasia Tumors inother mammary glands DCIS? Tumor focus Tognon et al, Cancer Cell, 2002; Li et al, Cancer Cell, 2007 Human secretory breast carcinoma Tognon et al, Cancer Cell, 2002 Breast cancer in Etv6-NTRK3 knockin mouse Li et al, Cancer Cell, 2007 Proof of the oncogenicity of ETV6-NTRK3: different features of secretory breast carcinomas arising in the same ETV6-NTRK3 mouse model
- 12. Normal physiological functionsof NTRK1/2/3 (TRKA, B, and C) PLCy MAPK PI3K Pain Thermoregulation Movement Memory Appetite Metabolic homeostasis Proprioception NGF/ NT3 BDNF / NT4 NT3 Ligand binding domain Kinase domain Ligand dependent phosphorylation P P NTRK1/2/3 gene TRKA/B/C protein P P
- 13. The advent ofnext generation sequencing has identified numerous other gene fusion variants involving all three NTRK genes, and across multiple tumor types Vaishnavi A, et al. Cancer Discov. 2015;5:25-34. Drilon A, et al. N Engl J Med. 2018;378:731-739.
- 14. - LMNA-NTRK1 oncogenicfusion in a soft tissue sarcoma in 41 yo female
- 15. NTRK fusions involvemany different partner genes and in different diseases with high clinical unmet need Adult Pediatric/Young adult Papillary thyroid cancer3,4 • NTRK1 fusion frequency: 11.8% • ETV6-NTRK3 fusion frequency (post-Chernobyl): 14.5% Intrahepatic cholangiocarcinoma6 • NTRK1 fusion frequency: 3.6% Glioblastoma multiforme1 • NTRK1 fusion frequency: 1% Secretory breast cancer5 • NTRK3 fusion frequency: 92% Mammary analogue secretory cancer2 • NTRK3 fusion frequency: >90% Pilocytic astrocytoma8 • NTRK2 fusion frequency: 3.1% Pediatric high-grade glioma7 • NTRK1/2/3 fusion frequency: 10% Congenital fibrosarcoma9,10 • NTRK3 fusion frequency: 91–100% Congenital mesoblastic nephroma (cellular subtype)10-11 • NTRK3 fusion frequency: 83–92% NTRK gene fusion frequencies reported from isolated case reports which used variable methodologies to detect these genetic alterations
- 16. • NTRK1-3 fusionsassociated with many different human cancers – At least 25 different tumor types, including breast cancer, ovarian cancer, colorectal cancer, melanoma, and lung cancer – Implicated in up to 1% of all solid tumor malignancies – NTRK gene fusions result from gene translocation events • Result in overexpression and constitutive ligand- independent activation of NTRK kinase domains All three NTRK genes implicated in oncogenic fusions • Suggested the possibility of targeting all 3 NTRKs with the same drug
- 17. Miracle in theMaking Ted Taylor GBM Survivor
- 18. The Diagnosis • ER2x Severe Headaches • Dr. 1x • Final ER insist • Receiving the news • Surgeon next day • Surgery 6 days later Oct 31, 2018 • Research begins! • Sat down Nov. 26, 2018 News
- 19. Research Vitrakvi • Beganresearch discovered 1% • Brought Vitrakvi to my Oncologists • Not available in Canada but step 1 was that I needed genetic testing. • Foundation One Cambridge, Massachusetts • Result verification needed fore & background. • Oncologist & Pharmacist application to Health Canada
- 20. Approval Process • HealthCanada approval Special Access Program as an initial patient for Larotrectinib • Bayer required the Foundation One report • Bayer approval • Shipped from UK to Germany to Vancouver and awaited shipment at the pharmacy • Began taking capsule on Good Friday 2019
- 21. Hope • Efficacy 7522 Complete initial response • Nothing like this ever before • TMZ largest breakthrough in 15 years - weeks • Standard of Care 14.6 months for my median survival with all achievements in human history. • In most cases optimal treatment, patients have a median survival of less than one year, there is no cure and a high rate of recurrence. Only 25% of patients survive more than one year. The U.S. National Center for Biotechnology Information (NCBI) lists long term survival beyond three years limited to less than 2% of patients. 98% chance you do not make it.
- 22. Side Effects &Adjustments • Take Vitrakvi 2x per day with breakfast and dinner daily. • Side effects Increased liver enzymes AST & ALT • Liver enzymes – my research (In trials some had to stop – be your own best advocate) • Water intake, 3L,4L,5L adjustments, Bilirubin's
- 23. ALT Before Adjusting Waterand Bilirubin’s graph is Parabolic
- 24. AST After Adjustments Normalrange or slightly above – Be your own best advocate.
- 25. Side Effects &Adjustments • Juxtapose against Standard of Care. TMZ reaction & immune, Red, White, Platlets. 6x Platlet Transfusions. Radiation 60 gy. Was told 100% I would lose my hearing in right ear. Increase radius of additional 2.5cm Fatigue, stamina, memory Not the same person but blessed to be alive and kept calm, friendly personality.
- 26. Liquid vs. Capsule • April19, 2019 started Capsule Vitrakvi • September 07, 2019 started liquid. (Health Canada approval July 31, 2019; but, approval was only for the liquid version). • Purpose dose vs. practical impact for adults • Worked with Health Canada to work towards capsules being approved. Back to capsules December 2020.
- 27. Scans & Results •Scans and results - Midline shift. Tumor location shrinking • Personal Impact on me – save • Comparison
- 28.
- 29. 1% and theFuture • 1% • 100 people watching • How many doctors watching with how many patients with any solid form cancers? • Future of medicine get tested. No matter how up to date your oncologists and doctors are they simply cannot know every new drug or treatment. Research and become your own best advocate. Work with receptive oncologist
- 30. Personal Impact • WhatCan I do? • Be your own best advocate • I want to help others. • Keto, Boswellia-Dex, • Hyperthermia • Exercise • Stay at peace • Relax time, walks, family & friends • Quiet time
- 31. Glioblastoma Guide www.glioblastomaguide.com YouTube Channel:Glioblastoma Guide
- 32. Thank You My Oncologists,Pharmacist, Surgeon, support of my family, friends, and all those who helped make Vitrakvi possible which is part of my “Miracle in the Making”
- 33. Canadian Cancer SurvivorNetwork Contact Info 1750 Courtwood Crescent, Suite 210 Ottawa, ON K2C 2B5 Telephone / Téléphone : 613-898-1871 E-mail: [email protected] or [email protected] Website: www.survivornet.ca Twitter: @survivornetca Facebook: www.facebook.com/CanadianSurvivorNet Instagram: @survivornet_ca Pinterest: http://pinterest.com/survivornetwork/