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
Median survival
NSCLC without activating mutation
>2 years
NSCLC with activating mutation (EGFR, ALK, ROS1)
>3 years
Breast Cancer ER-positive
4-5 years
Breast Cancer HER2-positive
Breast Cancer Triple negative
2 years
Melanoma BRAF mutant without immunotherapy
Melanoma with immunotherapy
>3-4 years

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):  

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: /ijms

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 Stud 3: a001115

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

27. ALK Inhibitors Can Also Control Leptomeningeal NSCLC
41 yo M 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
Leptomeningeal carcinomatosis identified
Ceritinib started
Symptoms resolved, stable/improved MRI
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