PracticeUpdate Oncology February 2019

EXPERT OPINION 18

Brain Metastases: A Brave New World By Rupesh R. Kotecha MD

Dr. Kotecha is Radiation Oncologist at Miami Cancer Institute, Baptist Health South Florida, and Assistant Professor at FIU Herbert Wertheim College of Medicine in Miami, Florida.

Brain metastases are the most common malignancies encountered in the central nervous system. There are approximately 200,000 to potentially 400,000 new cases diagnosed every year, and approximately 30% to 40% of all cancer patients will develop brain metastasis at some point during the course of their disease. We are seeing this more often because patients are living longer thanks to advances in surgery and systemic therapy. C learly, as patients are living longer, monitoring for intracranial pro- gression and developing systemic has been associated with response rates that range between 40% and 60% in some studies, mostly in patients who have mela- noma brain metastases.

among this patient population and those who receive immunotherapy have been significantly longer than what has been seen in historical controls. Currently, at our institution, we are performing research looking at the combination of radiosurgery and immunotherapy and the associated response rates and outcomes, and we are currently using this combination approach to maximize outcomes for every patient who we treat. Other emerging targeted therapies The advancements in terms of other tar- geted therapies have been made in the realm of brain metastases from non-small cell lung cancer, from breast cancer, and from melanoma. Non-small cell lung cancer The first-generation tyrosine kinase inhibi- tors – examples being erlotinib and gefitinib – that have been used in patients who have EGFR-mutated non-small cell lung cancer and brain metastases have been associated with response rates typically on the order of 50% to 80%. More exciting are the results of recent trials looking at the use of osimertinib and other third-genera- tion tyrosine kinase inhibitors, which have

therapies that have intracranial penetration will be key to preventing brain metastases from forming in the first place and to recog- nizing them at early stage when there are many treatment options available.

Given the response rates seen in these studies, we have to consider the true role of immunotherapy in patients who have brain metastases. This has put the treatment par- adigm in a state of flux for patients with newly diagnosed disease, especially when they have small lesions that are asympto- matic. There is now consideration given to the role of upfront immunotherapy in very select patient populations, namely those who have metastases that are small – typ- ically less than 1 to 2 cm – whose lesions are asymptomatic, who have very little edema, and who do not need steroids or any surgical or radiosurgical intervention. The next generation of studies will have to determine whether this approach of upfront systemic therapy alone, the use of radiosurgery alone, the use of radiosurgery and concurrent immunotherapy, or the use of immunotherapy and delayed radiosur- gery will truly become the next standard of care in this patient population. These data are exciting for patients with brain metastases, and survival outcomes

Role of immunotherapy and breakthroughs in treatment

Immunotherapies consist of drugs that tar- get the immune surface proteins, including the CTLA-4 inhibitors. More recently, inhib- itors against PD-1 and PD-L1 have been developed and evaluated for treatment in patients who have primarily lung cancer or melanoma brain metastases. Recently, in a phase II trial looking at the role of ipilimumab, the demonstrated control rates have been around 25%. There have been corresponding phase II trials with pem- brolizumab that have also shown response rates in the same ballpark, approximately 20% in patients who have melanoma and 30% in patients who have non-small cell lung cancer. Even more impressive is the combi- nation of these two therapy types, and the combination of ipilimumab and nivolumab

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