What’s New in Oncology: Precision Medicine for Brain Metastases as an Example

1. What’s New in Oncology: Precision Medicine for Brain Metastases as an Example Adam L. Cohen, MD, MS Assistant Professor Division of Oncology Department of Internal Medicine Huntsman Cancer Institute Adjunct Assistant Professor Department of Neurosurgery University of Utah School of Medicine May 16, 2018

2. Disclosures • I will discuss off label use of medications. • I receive research funding for clinical trials from BMS, Cascadian, Abbvie, Pfizer, Novartis, Cantex, the Musella Foundation, and the NIH.

3. Goals • Understand the epidemiology and prognosis of metastatic cancer in Utah • Understand the impact of precision medicine in oncology • Apply precision medicine to brain metastases in lymphoma, breast cancer, and lung cancer

5. What is the median survival for metastatic: • NSCLC? • Breast Cancer? • Melanoma? • < 1 year • 1-2 years • 2-4 years • > 4 years

6. Overall survival of metastatic cancers

7. Precision Medicine • Rational approaches to individualize targeted therapy regimens • Choose the right drug for the tumor, for the organ, and for the person

8. Example of Precision Medicine: Lymphoma • CLL/SLL is a disease of B-cell maturation • BTK is necessary for B-cell maturation • Ibrutinib is a small molecule inhibitor of BTK that is highly effective in CLL/SLL N Engl J Med. 2015 Dec 17;373(25):2425-37. 

9. Example of Precision Medicine: Lymphoma • 69 year-old man diagnosed with a PCNSL in 2012

10. Example of Precision Medicine: Lymphoma • 69 year-old man diagnosed with a PCNSL in 2012 • Treated with RMPV and HIDAC and achieved CR

11. Example of Precision Medicine: Lymphoma • 69 year-old man diagnosed with a PCNSL in 2012 • Treated with RMPV and HIDAC and achieved CR • Relapsed 4/2016

12. Example of Precision Medicine: Lymphoma • 69 year-old man diagnosed with a PCNSL in 2012 • Treated with RMPV and HIDAC and achieved CR • Relapsed 4/2016 • Treated with IT rituximab and achieved CR

13. Example of Precision Medicine: Lymphoma • 69 year-old man diagnosed with a PCNSL in 2012 • Treated with RMPV and HIDAC and achieved CR • Relapsed 4/2016 • Treated with IT rituximab and achieved CR • Relapsed 10/2016

14. Example of Precision Medicine: Lymphoma • 69 year-old man diagnosed with a PCNSL in 2012 • Treated with RMPV and HIDAC and achieved CR • Relapsed 4/2016 • Treated with IT rituximab and achieved CR • Relapsed 10/2016 • Treated with ibrutinib and achieved CR

15. Precision Medicine for Brain Metastases in Solid Cancers • Breast Cancer • NSCLC

16. Breast Cancer is More than One Disease Nature. 2012 Oct 4;490(7418):61-70

17. HER2 Pathway in Breast Cancer • HER2- positive breast cancer is HER2-driven and HER2-addicted. • Median survival of HER2 positive metastatic breat cancer in clinical trials of HER2-targeted therapy is 5 years Int. J. Mol. Sci.2016, 17(12), 2095; doi:10.3390/ijms17122095

18. Systemic Therapy for HER2-Positive Brain Metastases • Capecitabine (oral chemotherapy) and lapatinib (oral small molecule inhibitor of HER2) • LANDSCAPE: Phase 2 trial in women with brain metastases • Response rate 66%

19. Intrathecal Trastuzumab for Leptomeningeal Carcinomatosis • 17 case reports • Ongoing Phase I/II trial in France • Survival greatly exceeds historical standards (12 week median survival)

20. Precision treatment for HER2-positive brain metastases • 70 year-old woman with metastatic HER2-positive breast cancer. • 1/2016 developed headaches and found to have multiple brain metastases • 2/2016 Whole brain radiation, 15 fractions. • 10/2016 Progression of brain metastases

21. Precision treatment for HER2-positive brain metastases 4/2016 10/2016

22. Precision treatment for HER2-positive brain metastases • 70 year-old woman with metastatic HER2-positive breast cancer. • 1/2016 developed headaches and found to have multiple brain metastases • 2/2016 Whole brain radiation, 15 fractions. • 10/2016 Progression of brain metastases • Enrolled on a clinical trial of high dose trastuzumab and pertuzumab

23. Precision treatment for HER2-positive brain metastases 10/2016 6/2017

24. ASCO 2017 Interim Data J Clin Oncol 35, 2017 (suppl; abstr 2074)

25. ALK Mutated NSCLC • Activating ALK rearrangements occur in ~5% of NSCLC • More common in young males with little to no smoking history Cold Spring Harb Mol Case Stud3:a001115

26. ALK Targeting Small Molecules • Crizotinib (2011) • Ceritinib (2014) • Alectinib (2015) • Brigatinib (2017) N Engl J Med. 2017 Jun 6. doi: 10.1056/NEJMoa1704795. [Epub ahead of print]

27. ALK Inhibitors Can Also Control Leptomeningeal NSCLC 41 yoM never smoker • March 2014 • Metastasis to lungs, bone, brain, retina • Treated with Paclitaxel Carboplatin • ALK later identified and crizotinib added to chemo (pneumonitis) • May 2015 • Facial +arm numbness • Leptomeningealcarcinomatosis identified • Ceritinib started • Symptoms resolved, stable/improved MRI • 2015-2017 • working full time • June 2017 • Progressed in brain Slide courtesy of Dr. Wally Akerley

28. Conclusions • Cancer survival is changing due to precision medicine treatments • Effective agents that penetrate the brain can delay or replace local therapy for brain metastases and extend survival • Much work remains on extending the length of response to targeted agents and on improving biomarkers for predicting response.

29. Thank You