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

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.

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

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

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

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

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. 

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

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

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

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

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

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

Precision Medicine for Brain Metastases in Solid Cancers Breast Cancer NSCLC

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

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

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%

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

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

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

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

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

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

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

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]

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 2015-2017 working full time June 2017 Progressed in brain Slide courtesy of Dr. Wally Akerley

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.

Thank You