PracticeUpdate Oncology February 2019

EXPERT OPINION 19

" …the diagnosis of brain metastasis is no longer dismal. We are entering a brave newworld with exciting advances in each of the management strategies for patients with brain metastases, and these advances are ready to be brought to the clinic. "

been a recognition of the importance of cognition as a factor in therapeutic selec- tion, leading to an overwhelming use of stereotactic radiosurgery in patients who have limited brain metastases as well as those with multiple brain metastases. This has been fueled by two recent seminal studies that continue to show the neuro- cognitive detriment associated with whole brain radiation therapy as is traditionally given. More recently, the R2G0614 trial evalu- ated the use of memantine in addition to whole brain radiation therapy compared with a placebo agent and traditional whole brain radiation therapy. Although the study didn’t meet its primary endpoint, there were other endpoints that were clinically and statistically significant, which are worth mentioning. First of all, the patients rand- omized to memantine had a longer time to cognitive decline as well as a reduced risk for cognitive failure. Another treatment approach called hip- pocampal-sparing whole brain radiation therapy was demonstrated in a single-arm phase II trial, R2G0933, to be associated with a reduction in decline in the Hop- kins Verbal Learning Test, Delayed Recall, scores compared with historical standards. To validate these findings, a 518-patient phase III trial, the NRG-CC001 trial, evalu- ated the use of amantadine and this new technique of hippocampal avoidance whole brain radiation therapy, with the primary outcome being the time to neuro- cognitive failure. As was presented this year at the Astro Annual Meeting and at the Society for Neuro-Oncology Annual Meeting, there were significant improvements in the patients who underwent the hippocampal avoidance approach and also received memantine. In summary, the diagnosis of brain metas- tasis is no longer dismal. We are entering a brave new world with exciting advances in each of the management strategies for patients with brain metastases, and these advances are ready to be brought to the clinic. www.practiceupdate.com/c/77110

along with a small-molecule tyrosine kinase inhibitor, lapatinib, directed against the HER2 receptor. We have an ongoing trial under- way, the R2G1119 trial, which is a prospective study evaluating the role of either whole brain radiation therapy or stereotactic radio- surgery with or without lapatinib in patients who have HER2-positive breast cancer or brain metastases. In fact, the retrospective work that we have performed recently, and that I have submitted for publication, has shown that the combination approach with lapatinib and radiosurgery leads to improve- ments in local control. We will continue to learn more about the combination of these agents with radiation therapy and identify areas where we can either tailor the radiation dose or poten- tially delay radiation therapy in patients who have an excellent response to upfront systemic therapy. New-generation agents such as neratinib when added to other chemotherapies such as capecitabine have shown response rates that are impressive, approximately 50%, and other drugs that are going to be examined in this subgroup of breast can- cer patients will hopefully yield prospective data in the next year. Melanoma Patients with melanoma brain metastases are typically eligible for immunotherapy with a CTLA-4 inhibitor or a PD-1 inhibitor, either alone or in combination. However, the response rate to a BRAF inhibitor is modest among those patients who have BRAF mutations, who comprise approx- imately 50% of patients with systemic melanoma. The response rates range from 20% to 40% with either a BRAF inhibitor or a MEK inhib- itor alone; however, higher response rates are achievable with combination therapy, as we’ve seen in patients with HER2-posi- tive breast cancer. A combination approach is associated with a response rate of approximately 60%, with a favorable dura-

shown not only higher response rates but also more durable control of intracranial disease. Although the first-generation tyrosine kinase inhibitors such as crizotinib resulted in poor response rates (under 20% per- cent) in patients with non-small cell lung cancer with ALK rearrangements and brain metastases, the next generation of agents appears to have better penetration into the central nervous system, and the response rates, although seen in small studies, have been significantly higher, typically in the range of 50% to 80%. It would be very excit- ing to evaluate the role of these agents in prospective studies, either alone or in com- bination with radiotherapy. Breast cancer The development of HER2-directed agents represents a significant advancement for patients who have breast cancer. Tradition- ally patients who had HER2-positive disease had poor outcomes due to the aggressive nature of the disease. The development of trastuzumab and other HER2-directed sys- temic agents has significantly improved the outcomes for these patients. We are seeing that these patients have a high predilection for development of brain metastases, how- ever, and this is becoming an increasing part of our practice. For these patients, our department currently uses a combination approach with radiation treatment, typically stereotactic radiosurgery,

bility of at least 6 months. Neurosurgical advances

In regard to radiation treatment options for patients with brain metastases, there has

VOL. 3 • NO. 1 • 2019