Eudocia Q. Lee, MD
Novel agents are showing impressive ability to cross the blood–brain barrier (BBB) and impair tumor development in several malignancies, raising the prospect of achieving a long-elusive goal of anticancer therapy. With advancements in lung cancer leading the way, investigators are increasingly seeking to incor-porate into clinical trials patients who develop brain metastases from primary tumors else-where in the body.
The BBB, with its limited permeability to systemic treatment, has traditionally interfered with cancer treatments. Some chemotherapy agents can pass through the BBB to attack cancer cells, including temozolomide (Temodar), lomustine (Gleostine), and carmustine (BiCNU). However, chemotherapy is generally not as effective as surgery and radiotherapy (RT), which remain standard treatments for brain tumors. Recent advances with targeted therapies and immunotherapies have fueled optimism that systemic therapies can play an important role in brain tumor management. Major advances have been made in the central nervous system (CNS) penetrance of targeted therapies for ALK
-rearranged and EGFR
-mutant non–small cell lung cancer (NSCLC), HER2-positive breast cancer, and melanoma.
For further progress, the enrollment of patients with brain metastases in clinical trials is essential. Statistics show that a huge unmet need exists for effective therapies that can address these cancers. Each year, more than 200,000 patients receive a diagnosis of metastatic brain cancer. This cancer occurs most often in patients with advanced primary lung cancer but also is common in breast cancer and melanoma.1
Up to 50% of patients with lung cancer, 10% with melanoma, and 16% with breast cancer will develop secondary lesions in the brain. For many of these patients, survival may be measured in months rather than years (Table 1
“Historically, most trials of systemic ther-apies have excluded patients with brain metastases on the assumption that patients with brain metastases made poor clinical trial candidates,” said Eudocia Q. Lee, MD, senior physician and assistant professor of neurology at Dana-Farber Cancer Institute in Boston. “But there’s data that properly selected patients with brain metastases can participate in phase I studies and provide important information.”Multiple trials, many of which are detailed below, are providing important results to guide clinicians in the effective use of targeted therapies and immunotherapies, setting the stage for additional breakthroughs in the treatment of what remain highly therapy-resistant cancers.
Next-generation agents targeting ALK
-rearranged NSCLC are among the greatest success stories for achieving intracranial disease control with systemic agents, according to Ayal A. Aizer, MD, assistant professor of radiation oncology at Brigham and Women’s Hospital in Boston, Massachusetts. Among these drugs, there has been great improvement in a short amount of time.
“If you look at ALK
-rearranged NSCLC, crizotinib [Xalkori] had some potential but lagged in terms of intracranial efficacy relative to its systemic efficacy,” Aizer said. “The newer agents, like alectinib [Alecensa], ceritinib [Zykadia], and brigatinib [Alunbrig], have shown a lot of promise.”
In a retrospective analysis of the PROFILE 1005 and 1007 trials, crizotinib versus chemotherapy was associated with systemic and intracranial disease control in patients with ALK
-rearranged NSCLC and brain metastases. However, progression of intracra-nial lesions following initiation of crizotinib was observed in 20% of patients (51/253).3
Additionally, an analysis of single-patient findings from PROFILE 10014 illustrated crizotinib’s limited CNS activity. A low concentration of crizotinib was noted in the patient’s cerebrospinal fluid. “This was one of the first instances in the reported literature where we had a drug that has excellent systemic control in the body but, because of the blood–brain barrier, was not actually getting to the brain,” said Tejas Patil, MD, a hematology/oncology fellow at University of Colorado School of Medicine in Aurora. PROFILE 1001 began enrolling in 2008.
Thus, the development of second- and third-generation ALK tyrosine kinase inhibitors (TKIs) focused on increasing CNS penetrance and activity. The results of a randomized phase III trial5
showed that alectinib led to a greater rate of 12-month event-free survival (68.4% vs 48.7%) and fewer CNS progression events (12% vs 45%) than crizotinib in previously untreated patients with advanced ALK
-rearranged NSCLC. Additionally, the results of a phase III trial6
of patients with metastatic ALK
-rearranged NSCLC showed that 35% of the patients with brain metastases had an intracranial response with ceritinib (vs 5% who received chemotherapy).