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Systemic Therapy for Metastatic Disease

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Presented by Matthew Rioth, MD, MS. Presented at the 2018 Eyes on a Cure: Patient & Caregiver Symposium, hosted by the Melanoma Research Foundation's CURE OM initiative.

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Systemic Therapy for Metastatic Disease

  1. 1. Diagnosis and Management of Metastatic Ocular Melanoma Matthew Rioth MD, MS Assistant Professor of Medicine Division of Biomedical Informatics and Personalized Medicine Division of Medical Oncology Director of Clinical Cancer Informatics, UCHealth Colorado School of Public Health Department of Biostatistics and Informatics November 29, 2017
  2. 2. Disclosures • I have no relevant disclosures
  3. 3. Outline • Definitions • Imaging and biopsy • Liver-directed therapy • Systemic therapies • Future directions
  4. 4. What is metastasis? • The spread of cancer cells from the place where they first formed to another part of the body. • AKA “Stage four” cancer • Where? When? How?
  5. 5. All those scans… • Regular imaging and evaluation to detect early metastasis • Imaging liver and lung (and as directed by symptoms) • Options • Ultrasound • Computerized Tomography (CAT or CT) • MRI • Biopsy for confirmation
  6. 6. Ocular Melanoma vs Skin Melanoma Ocular • No BRAF mutation • Low mutational burden • Common liver metastases • No brain metastases • Common GNAQ/GNA11 mutation Skin • Common BRAF mutation • High mutational burden • Occasional liver metastases • Common brain metastases • Rare GNAQ/GNA11 mutation
  7. 7. Treating the Liver • Dr. Eschelman is talking about this in greater depth tomorrow • Several options for treating liver-only tumors • Surgery • Radioactive beads • Ablation • Chemotherapy perfusion
  8. 8. Systemic Therapies • Chemotherapy • Immunotherapy • Targeted therapy • Clinical trials
  9. 9. What is “Chemotherapy” • Drugs that inhibit or kill dividing cells • Cancer cells divide frequently, but so do others • This “off target” effect of chemotherapy causes side effects • Very narrow window to try to inhibit cancer cells without normal cells Sydney Farber, first demonstrated chemotherapy useful in pediatric leukemia in 1948. Image: Wikipedia
  10. 10. Cytotoxic chemotherapy in OM • Many different regimens of chemotherapy have been tested in metastatic ocular melanoma. • Commonly drugs such as dacarbazine are used in this context, but have underwhelming effectiveness. • In a review of multiple studies using chemotherapy, tumors took on average 2.6 months to start growing on chemotherapy. (JCO 34, no. 15_suppl (May 20 2016) 9567-9567) • Newer approaches are more frequently used now
  11. 11. What is Immunotherapy? • In addition to fighting bacteria and viruses, the immune system can also destroy cancer cells. • This probably happens more than we know, because the cells are destroyed before we ever detect them • In order to grow big, tumors must avoid being destroyed by the immune system.
  12. 12. xkcd.com/1907
  13. 13. Immunotherapy – Checkpoint Inhibitors Ipilimumab Pembrolizumab Nivolumab Atezolizumab JAMA. 2015;314(20):2117-2119
  14. 14. Checkpoint inhibitors in OM PLoS One. 2015; 10(3): e0118564. Cancer. 2016 Nov 15; 122(21): 3344–3353. J Immunother Cancer. 2018; 6: 13. Anti CTLA-4 (Ipilimumab) Anti PD-1 (Keytruda) Exceptional responders
  15. 15. What is targeted therapy? • Cancers are characterized by mutations (changes) in their DNA that give rise to cells that grow too much and/or die not enough. • Those mutations in the DNA can leave a tumor cell susceptible to drugs designed to inhibit those mutations.
  16. 16. Targeted Therapy Successes Blood. 2012 Mar 1; 119(9): 1981–1987. The Lancet Oncology 2014 15, 954-965 Gleevec in chronic myelogenous leukemia BRAF inhibitors in cutaneous melanoma
  17. 17. Genetics of Ocular Melanoma Br J Ophthalmol. 2017 Jan; 101(1): 38–44.
  18. 18. MEK inhibition in OM JAMA. 2014 Jun 18; 311(23): 2397–2405. Phase III SUMIT Trial: - No difference in tumor growth between selemetinib + chemotherapy versus selemetinib + placebo
  19. 19. Targeted therapies of the future Therapy Mechanism of action Phase Identifier Trial status Selumetinib+paclitaxel MEK1/2 inhibitor+chemotherapy II EudraCT: 2014-004437-22 Recruiting Trametinib+GSK21417 95 MEK inhibitor+AKT inhibitor II NCT01979523 Recruiting Binimetinib+AEB071 MEK inhibitor+PKC inhibitor I/II NCT01801358 Recruitment held Cabozantinib MET inhibitor II NCT01835145 Recruiting Vorinostat Histone deacetylase inhibitor II NCT01587352 Recruiting Sorafenib Multi-kinase inhibitor II NCT01377025 Recruitment complete Ganetespib HSP90 inhibitor II NCT01200238 Recruitment held Adoptive T-cell transfer Tumour-infiltrating lymphocytes II NCT01814046 Recruiting AEB071+BYL719 PKC inhibitor+PI3K inhibitor Ib NCT02273219 Recruiting AEB071 PKC inhibitor I NCT01430416 Recruitment complete Br J Ophthalmol. 2017 Jan; 101(1): 38–44.
  20. 20. Brief note on clinical trials Phase Objective Description 1 Is this new treatment safe? Outcomes relate to drug safety and tolerability. 2 Is this treatment effective? Outcomes relate to does the disease show a response to the treatment. 3* Is this treatment better? Often with two groups that are randomly assigned to determine if one treatment is better than another. 4 Is this treatment the best? Similar to phase 3 trials, but can look at longer times, other endpoints, more patients. *Often the results of a positive phase 3 trial are used in an application for FDA approval. Once FDA approval has been granted, then the therapy can be proscribed by any physician.
  21. 21. Future Directions • IMCgp100 • Hepatic perfusion • Tumor infiltrating lymphocytes • Novel or combination targeted therapies
  22. 22. IMCgp100 (“Immunocore drug”) • IMCgp100 is a drug in current phase II clinical trials for ocular melanoma. • This drug functions as an immunotherapy • Encouraging preliminary data demonstrating prolonged survival
  23. 23. IMCgp100 Mechanism of Action • IMCgp100 has two arms, one to grab the tumor cell and another to recruit immune cells to attack it. • The handle on the tumor cell is gp100, which is also present on skin melanocytes. • The handle on the immune cell is HLA- A*0201, which is present in about 50% of the population.
  24. 24. IMCgp100 safety and effectiveness • Most people will have skin rash with first few doses, some will develop over active immune system reaction and require intensive care. • After several doses these risks diminish substantially. • Preliminary data with IMCgp100 demonstrates about ~73% survival at 1 year, compared to ~35% with other published therapies.
  25. 25. Percutaneous Hepatic Perfusion (“Delcath”) • Current phase 3 clinical trial investigating high dose chemotherapy delivered directly to the liver vs dacarbazine; transarterial chemoembolization; ipilimumab; or pembrolizumab. • Patients with extra-hepatic tumor burden which is unable to be resected or radiated must not be included in the trial. http://delcath.com/about-the-technology/
  26. 26. PHP safety and effectiveness J Surg Oncol. 2017 Dec 28.
  27. 27. Tumor Infiltrating Lymphocytes (“TILs”) Nat. Rev. Immunol. 12, 269-281
  28. 28. Tumor Infiltrating Lymphocytes (“TILs”) Lancet Oncol. 2017 Jun;18(6):792-802
  29. 29. Novel or combination targeted therapies Br J Ophthalmol. 2017 Jan; 101(1): 38–44.

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