Systemic Options for Treating Brain Metastases

Linda Brookes, MSc

Disclosures

October 27, 2015

Brain metastases occur most commonly in patients with lung cancer, breast cancer, and melanoma. Until recently, systemic therapy has been seen to be of limited value in the management of brain metastases, but more encouraging results are now being obtained with targeted therapies, owing to greater understanding of molecular markers, genotyping, and the biology of brain metastasis. The current status of treatment and ongoing research were reviewed during an integrated session of the European Cancer Congress. All of the speakers criticized the lack of clinical research in brain metastasized cancers and called for more clinical trials to be carried out in these patient populations, noting that in the past these patients were excluded from many trials.

Brain Metastases in Lung Cancer

At least 40% of patients with non-small cell lung cancer (NSCLC) have brain metastases, noted Sanjay Popat, MRCP, PhD, a thoracic medical oncologist at the Royal Marsden Hospital, in London, United Kingdom. "In this difficult population," explained Dr Popat, "the biggest problem is that the traditional standard of care, whole-brain radiation therapy (WBRT), may be of little value in unselected patients, as demonstrated recently in the QUARTZ trial,[1] where WBRT provided no additional clinically significant benefit. However, systemic therapy can be active in selected NSCLC patients with brain metastases," he stressed.

Not all brain metastases are the same. "Not all brain metastases are similar in lung cancer," Dr Popat noted. "We are used to substratifying these patients at the genotype level, and the same should be considered true for brain metastases." Tyrosine kinase inhibitors (TKIs) against active oncogenes are highly active in brain metastases. Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, given with WBRT, appeared to have little activity in unselected NSCLC patients with brain metastases in the TACTIC trial[2] but resulted in marked benefit in patients with EGFR-mutated tumors.[3] A small subgroup analysis of the LUX-Lung 3 trial data suggested that another TKI, afatinib, potentially prevents or increases the time to brain progression in patients with EGFR-mutated NSCLC.[4]

"A common problem seen in the clinic is patients with established brain metastases and leptomeningeal disease with EGFR mutation," said Dr Popat. Cases have been reported of patients treated with pulsed TKI (erlotinib or gefitinib). One of the largest series involved weekly pulsed TKI therapy in EGFR-mutated central nervous system (CNS) disease.[5] "The response rate was 67%, and while the median time to CNS progression was small at 2.7 months, the upper limit of 14.5 months was potentially quite impressive for this difficult-to-treat population," Dr Popat reported.

NSCLC patients with genomic changes involving anaplastic lymphoma kinase (ALK) have a high propensity of brain metastases. A pooled analysis of data from the PROFILE 1005 and 1007 clinical trials suggested some activity for crizotinib, a multitargeted TKI with activity against ALK, in untreated or treated brain metastases that appeared to be augmented by prior radiation therapy.[6] Dr Popat pointed to evidence that second-generation ALK inhibitors have more activity in the brain. Data from the ASCEND-1 trial[7] showed that patients with brain metastases given ceritinib achieved an overall response rate (ORR) of 54%; for those who were ALK-inhibitor naive, the ORR was 69.2% vs 50% for those treated with a prior ALK inhibitor—results that Dr Popat considered "very impressive in patients with a high propensity for brain metastases." Similar "impressive" ORRs (42%-57%) have been reported with alectinib.[8] A TKI in development, brigatinib, was associated with a response rate "much higher than one would anticipate" in a population with intracranial CNS metastases previously treated with systemic chemotherapy, commented Dr Popat.[9] In a large retrospective cohort study, TKIs were associated with "very impressive" intracranial responses in patients with EGFR-mutated and ALK-rearranged NSCLCs.[10]

"It is possible to use a molecular agnostic approach, meaning therapy not based on the genotype," Dr Popat acknowledged. NSCLC brain metastasis formation is known to be vascular endothelial growth factor A (VEGF-A) dependent, so one potential approach is to inhibit VEGF-A in these lesions. This may have a role in either secondary prevention or at least limiting the effectiveness of the established metastasis through inhibition of co-option or neoangiogenesis. Bevacizumab, a humanized anti-human VEGF-A monoclonal antibody, is known to be safe in NSCLC with brain metastases, as evidenced by the PASSPORT trial,[11] in which patients received bevacizumab with either first- or second-line systemic therapy. "There are few data that support its effectiveness," Dr Popat noted, but recently the phase 2 BRAIN study reported an intracranial response rate of about 60%.[12]

Immune checkpoint inhibitors an option. There is a biological rationale for using immune checkpoint inhibitors for patients with NSCLC brain metastases, Dr Popat stated, because immune surveillance is known to be active within the brain, and lymphocyte trafficking is very important for antigen presentation within the brain. "We have learned from experience with ipilimumab in melanoma where the evidence of efficacy was limited to the patients who didn't require steroids,[13] although we do not know whether this was because steroids were associated with a worse prognosis, or a reduction in immune effects of the checkpoint inhibitor, or potential change to blood-brain barrier (BBB) permeability," Dr Popat admitted. The programmed cell death-ligand 1 (PD-L1) checkpoint inhibitor atezolizumab showed some activity "with a very good safety profile" in NSCLC patients with brain metastases similar to those without brain metastases in the FIR study.[14] Pembrolizumab, a programmed cell death protein 1 (PD-1) antibody, was recently reported as producing a 33% response rate with durable responses in a small number of patients with advanced NSCLC and untreated brain metastases.[15] "So at this stage, immune checkpoint inhibitors seem safe and active in small volume metastases without steroid dependency," Dr Popat concluded.

Brain Metastases in Breast Cancer

In patients with breast cancer, brain metastasis occurs in 10%-30% of patients. Systemic therapy seems to be a treatment option for some patients with breast cancer metastases, noted Matthias Preusser, MD, associate professor at the Medical University of Vienna, Austria. Continuous human epidermal growth factor 2 (HER2) blockade is recommended in HER2-positive breast cancer patients with brain metastases, and drugs that effectively target the HER2 alteration—trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1) —may be effective.

HER2-targeting agents show some activity. Due to its molecular weight, trastuzumab does not readily cross the intact BBB, but the situation is less clear where there is breakdown of the BBB including brain metastases, treated and untreated, Dr Preusser explained. Several studies have suggested that trastuzumab may cross the BBB in these cases,[16,17] and responses of brain metastases have been reported in the clinic, but prospective clinical trial data are lacking.

Uptake of lapatinib has been reported in brain metastases in breast cancer patients, although with a high variability in the concentrations reached within the brain metastases.[18] In a prospective clinical study, LANDSCAPE,[19] patients with HER2-positive breast cancer with previously treated or untreated metastases "showed very interesting CNS response rate of 65.9%; however, at the moment we do not have a follow-up trial comparing the regimen to established treatment options like WBRT," Dr Preusser cautioned. "At the moment we cannot answer the question as to whether we should use trastuzumab or lapatinib."

Few data are available with the newer HER2 blockers. Dr Preusser and his colleagues[20] recently reported a small study of T-DM1 in HER2-positive breast cancer brain metastases that showed promising responses (30% CNS response rate, 50% clinical benefit, and median progression-free survival [PFS] of 5 months) and good tolerability. "So we believe that a clinical trial with this drug would be of interest, but we need to be aware that when we use novel drugs in patients with brain metastases, unexpected toxicities may appear," he cautioned. He recalled that in one study, T-DM1 and stereotactic radiosurgery (SRS) resulted in clinically relevant brain edema in several cases.[21] He pointed out that "bevacizumab may be very useful in selected patients to reduce brain edema," having shown "substantial effects" in the clinical setting in brain metastatic breast cancer.[22]

Promising new drugs. Novel drugs under development in breast cancer brain metastases include CDK4/6 inhibitors, which bind to CDK4 and CDK6, blocking phosphorylation of the Rb protein and preventing G1 cell cycle progression. Brain penetration and favorable activity have been reported with abemaciclib in individual patients, and a phase 2 study[23] with abemaciclib is ongoing in patients with brain metastases from hormone receptor-positive breast cancer. Preliminary evidence suggests that ONT-380, a small-molecular selective HER2 inhibitor with minimal EGFR-like side effects, when given orally (300 mg twice daily), is active in heavily pretreated HER2-positive metastatic breast cancer patients with prior exposure to trastuzumab, pertuzumab, or T-DM1.[24]

"We must not forget that chemotherapy is still effective in some patients, so liposomal cytotoxic agents that have a higher likelihood of penetrating into the brain may be of some interest," Dr Preusser added. 2B3-101 (glutathione PEGylated liposomal doxorubicin) is being developed for patients with multiple brain cancer indications, with an initial focus on patients with brain metastases from breast cancer and patients with glioma. 2B3-101 is being investigated in a phase 1/2a clinical trial for various forms of brain cancer.[25]

Brain Metastases in Melanoma

Brain metastasis develops in approximately 50% of patients with metastatic melanoma. "There is no doubt that there is a high unmet medical need in these patients," said Dirk Schadendorf, MD, professor and chair in the Department of Dermatology at the University Hospital in Essen, Germany. "WBRT, considered standard of care, is associated with low response rates of about 10% and median survival between 3 and 6 months," Dr Schadendorf explained, adding that systemic treatments such as temozolomide have been used quite frequently in patients of all ages, and clinical data show response rates between 1% and 7% in the brain with short durations of response at 1-2 months.[26,27] In the past 5 years, Dr Schadendorf noted, six new drugs have become available for treatment of metastatic melanoma: ipilimumab, vemurafenib and dabrafenib (BRAF inhibitors), nivolumab and pembrolizumab (PD-1 inhibitors), and trametinib (MEK inhibitor).

Approval of ipilimumab in 2011 was on the basis of a study showing prolongation of overall survival (OS) of around only 3 months,[28] but this was reproducible, and clinical need was high at that time. A multicenter study then investigated ipilimumab (10 mg/kg in an unapproved regimen of four doses plus maintenance in patients with advanced melanoma and brain metastases).[29] "Response rates were low, but OS in neurologically asymptomatic patients was reasonably good, at 31% survival at 1 year and 26% at 2 years, but this was a highly selected patient population and whether these are real-world data is questionable," Dr Schadendorf cautioned. "If you look at ipilimumab given at its licensed dose of 3 mg/kg given in 145 patients from the Italian Expanded Access Program, you see that median PFS is 2.9 months, and median OS is 4.6 months for that patient population, with only 19% of patients alive after 1 year.[30] That is probably a realistic picture of what ipilimumab can achieve in melanoma brain metastases; and usually if there is a certain tumor burden, then ipilimumab is not the best choice for treating those patients."

The role of PD-1 inhibitor combinations in melanoma brain metastases remains open, Dr Schadendorf said. Clinical data are not expected from the first studies of nivolumab/ipilimumab combination in these patients until early 2016. CheckMate 204,[31] a phase 2 study ongoing in the United States, is evaluating nivolumab/ipilimumab followed by nivolumab monotherapy. Approximately 50% of 110 patients enrolled in this study are expected to have had prior stereotactic radiation therapy. An open-label study of vemurafenib in patients with BRAFV600 mutation-positive melanoma reported intracranial and extracranial responses.[32] Early data from a phase 2 trial with vemurafenib showed few complete responses (1%), but partial response (18%) and stable disease (42%) rates were higher.[33] An open-label, single-arm, multicenter study is evaluating the efficacy and safety of vemurafenib oral doses of 960 mg orally twice daily in previously treated or untreated melanoma with brain metastases.[34] Dabrafenib has been investigated as monotherapy (150 mg twice daily) in the phase 2 open-label BREAK-MB study,[35] which enrolled 172 patients with BRAFV600 mutation-positive melanoma and showed overall disease control (complete response + partial response + stable disease) of over 80% in both treated and untreated groups. Compared with the "very depressing results" seen with temozolomide,[26] in BREAK-MB dabrafenib was associated with a doubling of OS and an extension in PFS from 1 month to over 16 weeks. "There is clear evidence that there is an impact of targeted therapy on melanoma brain metastases," concluded Dr Schadendorf.

"Current guidelines stress that the mutational status of the melanoma tissue is of critical importance and that it also dictates what kind of treatment should be recommended. Systemic treatment options do not differ whether the patient has brain metastases derived from extracranial disease," Dr Schadendorf said. "Treatment decisions we are making today depend on performance status (neurologic symptoms from individual lesions), metastasis growth and speed of development, and mutational status (BRAF)," he advised.

Outlook for Treatment and Prevention

The current lack of efficacy with any chemotherapy or molecular agent in the treatment of brain metastases is thought to be due, in part, to the heterogeneous permeability of the BBB, explained Patricia S. Steeg, PhD, senior investigator at the Center for Cancer Research at the National Cancer Institute (NCI), in Bethesda, Maryland. Although little is known about how heterogeneous permeability develops or how it varies among individual metastases, understanding the BBB's role in metastasis will be crucial to the development of new, more effective therapies.

"We either have to come up with some brain-permeable drugs, or we are only going to be treating the 10% of lesions that are permeable, or we are going to have to alter brain permeability," Dr Steeg stated. She reported that NCI investigations of over 30 drugs in model systems have identified few effective compounds. "None has shrunk established lesions, although four of them—lapatinib, saracatinib/lapatinib, pazopanib, and low-dose temozolomide—had partial preventive activity," she said. "Each of these will prevent brain metastases from forming, but none of them will shrink an established lesion, at least to any significant degree."

Most designs for clinical trials in brain metastasis patients evaluate progression after WBRT, Dr Steeg noted. Patients are easy to recruit for these trials, and the endpoint is lesion shrinkage. Other trials look at therapy concurrent with WBRT—"the elusive radiation sensitizers"—with the same endpoint.

"We can think about prevention, where the endpoint would be time until brain metastasis, but no one is sure who to recruit for these trials. The trials would also be very expensive and take a lot of time," Dr Steeg admitted. She foresees more opportunity with secondary prevention trials, which would look at prevention of additional metastases in patients with limited brain metastases. Such trials are ongoing, including a phase 2 study at the University of Maryland that is looking at SRS followed by systemic therapy (physician's choice) plus HER2-directed therapy (trastuzumab, pertuzumab, T-DM1, or lapatinib) in HER2-positive breast cancer patients with one to 10 brain metastases.[36] The aim of this trial is to determine whether such treatment will result in a 6-month distant brain relapse rate of less than 30%.

The NCI is currently drafting what Dr Steeg calls a "pick the winner" trial in HER2-positive breast cancer patients with one to five brain metastases treated with SRS or surgery but not WBRT. Patients will receive T-DM1 as systemic therapy followed by metronomic temozolomide or low-dose pazopanib. The endpoint of this trial will be the percentage of patients who develop a new metastasis outside of the SRS bed at 6 months, not shrinkage of the existing tumor. For the future, Dr Steeg foresees that therapeutic targets will focus on crosstalk between the tumor cells and the brain microenvironment (the "seed and soil" theory). "These are not the usual suspects, like HER2 and EGFR," she said. "If we go after these, we might have something."

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