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The TRK to Tumor - Agnostic Care in Solid Tumors A Pathology - Focused Guide to the Clinical Role of TRK Fusions in Personalizing Cancer Therapy Anna F. Farago, MD, PhD, Assistant in Medicine Massachusetts General Hospital Assistant Professor

  1. The TRK to Tumor - Agnostic Care in Solid Tumors A Pathology - Focused Guide to the Clinical Role of TRK Fusions in Personalizing Cancer Therapy Anna F. Farago, MD, PhD, Assistant in Medicine Massachusetts General Hospital Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts 1 Disclosures Anna F. Farago, MD, PhD, has a financial interest/relationship or affiliation in the form of: Consultant For: AbbVie Inc.; AstraZeneca; Bayer; Genentech, Inc.; Loxo Oncology; PharmaMar; Boehringer Ingelheim; Roche; and Bristol-Myers Squibb. Speakers Bureau participant with: Foundation Medicine, Inc. Anna F. Farago, MD, PhD, does intend to discuss any non-FDA-approved or investigational use of the following products/devices: entrectinib, repotrectinib; LOXO-195. This CME/MOC activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. This activity is supported by an independent educational grant from Bayer and Loxo Oncology. 2 Visit us at PeerView.com/TRKpath • Download the slides and Practice Aids • Apply for CME/MOC credit • Request a live meeting at your institution Join the Join the conversation on conversation on Need more information? Twitter @PeerView Twitter @PeerView Send an email to live@PeerView.com 3

  2. Genotype-Directed Therapy 1 1. Mitsudomi T et al. Nat Rev Clin Oncol. 2013;10:235-244. 4 Molecular Classification of Lung Cancer 1 1. Jordan EJ et al. Cancer Discov. 2017;7:596-609. 5 Types of Somatic Genomic Alterations in Cancers Alteration Common Examples EGFR mutations Point mutations, Point mutations, KRAS mutations short insertions, or deletions (indels) short insertions, or deletions (indels) BRAF mutations HER2 Copy number alterations Copy number alterations amplification MET amplification BCR-ABL Gene fusions Gene fusions ALK fusions NTRK fusions 6

  3. NTRK and TRK Terminology GENES: PROTEINS: NTRK1 TRKA NTRK2 TRKB NTRK3 TRKC 7 TRK Biology and Signaling in the Nervous System 1 1. Cocco E et al. Nat Rev Clin Oncol . 2018;15:731-747. 8 Schematic of Gene Fusion Leading to Activation 1,2 1. https://www.cancer.gov/news-events/cancer-currents-blog/2016/leukemia-infant-research-model. Accessed May 14, 2018. 2. Farago AF, Azzoli CG. Transl Lung Cancer Res . 2017;6:550-559. 9

  4. Schematic of Gene Fusion Leading to Activation (Cont’d) 1,2 1. https://www.cancer.gov/news-events/cancer-currents-blog/2016/leukemia-infant-research-model. Accessed May 14, 2018. 2. Farago AF, Azzoli CG. Transl Lung Cancer Res . 2017;6:550-559. 10 Schematic of Gene Fusion Leading to Activation (Cont’d) 1,2 1. https://www.cancer.gov/news-events/cancer-currents-blog/2016/leukemia-infant-research-model. Accessed May 14, 2018. 2. Farago AF, Azzoli CG. Transl Lung Cancer Res . 2017;6:550-559. 11 TRK Fusion Cancers as an Example of Fusion-Driven Cancer Pathogenesis 1,2 Signal Cell Growth and Proliferation Cascade Dimerization of Chimeric Protein As a result, TRK fusion proteins are constitutively Oncogenic fusions Oncogenic fusions Allows kinase portions of Allows kinase portions of active due to ligand- of NTRK genes retain the of NTRK genes retain the the TRK proteins to the TRK proteins to independent activation kinase domain of TRK kinase domain of TRK autophosphorylate autophosphorylate and propagate a constant but cause constitutive but cause constitutive independent of any independent of any signal cascade that causes dimerization/activation dimerization/activation regulation 1,2 regulation 1,2 cells to overproliferate and survive 1,2 1. Amatu A et al. ESMO Open . 2016;1:e000023. 2. Vaishnavi A et al. Cancer Discov . 2015;5:25-34. 12

  5. Estimated Frequency of TRK Fusions Across Tumor Types 5%-25% ≥75% • Congenital mesoblastic • Mammary analogue secretory nephroma 1,2 carcinoma (MASC) of the salivary gland 8 • Recurrent papillary thyroid cancer 3 • Secretory breast carcinoma 9 • Pontine glioma 4 • Infantile fibrosarcoma 10 • Spitzoid melanoma 5 • Pediatric and young adult soft tissue sarcomas 6 • Pan-negative gastrointestinal stromal tumors (GIST) 7 1. Argani P et al. Mod Path. 2000;13:29. 2. Rubin BP et al. Amer J Path. 1998;153:1451-1458. 3. Leeman-Neill RJ et al. Cancer. 2014;120:799-807. 4. Wu G et al. Nat Genet. 2014;46:444-450. 5. Wiesner T et al. Nat Commun . 2014;5:3116. 6. Morosini D et al. 2015 American Society of Clinical Oncology Annual Meeting (ASCO 2015). Abstract 11020. 7. Brenca M et al. J Path . 2016;238:543-549. 8. Bishop JA et al. Hum Pathol. 2013;44:1982-1988. 9. Tognon C et al. Cancer Cell. 2002 ; 2:367-376. 10. Bourgeois JM et al. Am J Surg Pathol . 2000;24:937-946. 13 Estimated Frequency of TRK Fusions Across Tumor Types (Cont’d) ≤5% CNS Lung • Astrocytoma 1 • Adenocarcinoma 2,7 • Low-grade glioma 2 • Large cell neuroendocrine carcinoma 8 • Glioblastoma 3 GI Other • Colorectal cancer 2,4 • Acute myeloid leukemia 9 • Cholangiocarcinoma 5 • Breast-invasive carcinoma 2 • Pancreatic cancer 6 • Melanoma 2 Head and neck • Sarcoma 2 • Squamous cell carcinoma 2 1. Jones DT et al. Nat Genet. 2013;45:927-934. 2. Stransky N et al. Nat Commun. 2014;5:4846. 3. Kim J et al. PLoS One. 2014;9:3. 4. DeBraud F et al. ASCO 2014. Abstract 2502. 5. Ross JS et al. Oncologist. 2014;19: 235-242. 6. Bailey P et al. Nature. 2016;531:47-52. 7. Vaishnavi A et al. Nat Med. 2013;19:1469-1472. 8. Fernandez-Cuesta L et al. 2014 American Association of Cancer Annual Meeting (AACR 2014). Abstract 1531. 9. Kralik JM et al. Diag Path . 2011;6:19. 14 Detection of TRK Fusions Detection of TRK Fusions 15

  6. Methods for Detection of TRK Fusions 1-4 IHC Hechtman et al:  Rapid results • TRK IHC assessed using pan-Trk  Detects monoclonal antibody clone EPR17341 transcribed and (Abcam) translated events Advantages only • Tested on 23 available NTRK fusion cases  Low cost as single and 20 consecutive tumors without evidence of NTRK fusion test • IHC was concordant with Archer RNA − Depletion of testing in 21 of 22 cases tissue • IHC sensitivity 95.2%, specificity 100% Fusion partner − and position Disadvantages unknown − Less well- validated currently 1. Jordan EJ et al. Cancer Discov . 2017;7:596-609. 2. Hyman DM et al. ASCO 2017. Abstract LBA2501. 3. Farago AF et al. J Thorac Oncol . 2015;10:1670-1674. 4. Hechtman JF et al. Am J Surg Pathol . 2017;41:1547-1551. 16 Methods for Detection of TRK Fusions (Cont’d) 1-4 IHC FISH  Rapid results  Rapid results  Detects transcribed and translated events Advantages only  Low cost as single test Depletion of Depletion of − − tissue tissue − Fusion partner − Fusion partner and position and position Disadvantages unknown unknown − Less well- − Can be difficult to validated currently interpret 1. Jordan EJ et al. Cancer Discov . 2017;7:596-609. 2. Hyman DM et al. ASCO 2017. Abstract LBA2501. 3. Farago AF et al. J Thorac Oncol . 2015;10:1670-1674. 4. Hechtman JF et al. Am J Surg Pathol . 2017;41:1547-1551. 17 Examples of IHC and FISH 1,2 Take-home point: Techniques with faster results, such as IHC/FISH, may be useful in cancers in which the likelihood of a TRK fusion is high 1. Hyman DM et al. ASCO 2017. Abstract LBA2501. 2. Farago AF et al. J Thorac Oncol . 2015;10:1670-1674. 18

  7. Methods for Detection of TRK Fusions (Cont’d) 1-4 IHC FISH NGS  Rapid results  Rapid results  Potential for  Detects multiplexed transcribed and testing translated events  Less depletion Advantages only of tissue  Low cost as single  Fusion partner test and position are defined Depletion of Depletion of Longer wait time − − − tissue tissue for results Fusion partner Fusion partner Cost − − − and position and position Disadvantages unknown unknown Less well- Can be difficult to − − validated currently interpret 1. Jordan EJ et al. Cancer Discov . 2017;7:596-609. 2. Hyman DM et al. ASCO 2017. Abstract LBA2501. 3. Farago AF et al. J Thorac Oncol . 2015;10:1670-1674. 4. Hechtman JF et al. Am J Surg Pathol . 2017;41:1547-1551. 19 Next-Generation Sequencing 1 1. Meyerson M, Getz G. Nat Rev Genet. 2010;11:685-696. 20 DNA- vs RNA-Based NGS Approaches 1,2 DNA-based NGS RNA-based NGS  Potential for multiplexed assessment for multiple  Potential for multiplexed assessment for multiple different fusion targets different fusion targets o Detected fusions may or may not be expressed  Detection of expressed transcripts o Requires tiling through intronic regions  Read directly through expressed transcripts o Fusion positions are inferred based on reads  Fusion positions are directly demonstrated through genomic DNA 1. Meyerson M, Getz G. Nat Rev Genet. 2010;11:685-696. 2. Zheng Z et al. Nature Med. 2014;20:1479-1484. 21

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