Making Progress Against the Blood-Brain Barrier

OncologyLive, Vol. 23/No. 2, Volume 23, Issue 02

Primary and metastatic brain tumors present a significant therapeutic challenge, in large part because they are protected by the blood-brain barrier, a highly restrictive interface between the bloodstream and the brain that prevents most drugs from accessing the brain parenchyma.

Primary and metastatic brain tumors present a significant therapeutic challenge, in large part because they are protected by the blood-brain barrier (BBB), a highly restrictive interface between the bloodstream and the brain that prevents most drugs from accessing the brain parenchyma.1

Despite decades of research, our understanding of the BBB is still incomplete. Adding to the complexity are the changes the BBB undergoes during tumorigenesis, which are even less well understood, particularly their effect on the ability of therapeutics to access the brain.1

Nevertheless, persistent efforts by investigators and pharmaceutical companies to find ways to breach the BBB and improve the treatment of brain tumors, as well as the growing inclusion of patients with active brain metastases in clinical trials, have brought about significant advances.2-4

These include the FDA’s April 2020 approval of tucatinib (Tukysa), a HER2-targeted tyrosine kinase inhibitor (TKI), in combination with trastuzumab (Herceptin) plus capecitabine for the treatment of patients with HER2-positive breast cancer, including those with brain metastases, after prior therapy.5 Investigators said the regimen is the first to demonstrate improved activity against brain metastases in a randomized clinical trial in patients with this tumor type.6

Much of the ongoing research focuses on honing the brain-penetrating capabilities of small-molecule drugs, which are more likely to be able to pass through the BBB.1 Numerous clinical trials testing TKIs in patients with brain metastases are underway, particularly in non–small cell lung cancer (NSCLC) and breast cancer.

Other strategies also are emerging. Immune checkpoint inhibitors are being evaluated in primary and metastatic brain tumors, most frequently in combination with other therapies. Additionally, investigators are concentrating on finding ways to disrupt or bypass the BBB to enhance drug delivery. In a technique termed ultrasound-induced blood-brain barrier disruption (US-BBBD), the acoustic pressure from focused ultrasound (FUS) is used to excite microbubbles, which leads to transient openings in the BBB that could facilitate drug delivery. Several ultrasound devices have been developed and, following promising preclinical findings, are now in the early stages of clinical testing in cancers with brain metastases.7

Enchancing Brain Penetration

Whether a molecule can penetrate the BBB is dependent on its size and physiochemical properties; nearly all large-molecule drugs and up to 98% of small-molecule drugs are thought to be unable to cross the BBB. Those that make it across the barrier may succumb to the activity of active efflux transporters that rapidly evict them.1,7

As our understanding of the BBB in the context of cancer has evolved, it has become clear that the BBB is altered by the presence of both primary and metastatic tumors in the brain. The brain-tumor barrier (BTB), as this cancer-modified BBB is known, is more permeable than the normal BBB. However, this does not appear to always work in favor of drug delivery because of the heterogeneous nature of these changes across the BTB.1

Brain metastases are the most common intracranial tumors in adults and a significant cause of morbidity and mortality. Across tumor types, metastasis to the brain occurs in an estimated 10% to 30% of patients, and its prevalence is believed to be increasing as treatments for extracranial disease become more effective.7-9

Brain metastases are particularly common in patients with lung cancer, breast cancer, renal cell carcinoma, and melanoma, with primary lung cancer accounting for approximately half of all cases.8-10

Although there have been significant advancements in the treatment paradigm for each of these cancer types in the past several decades, evidence of therapeutic efficacy against brain metastases has lagged in part because of the exclusion of patients with brain tumors from most clinical trials. This has begun to change in recent years; there was a steady decrease in the percentage of trials excluding patients with brain metastases from 2000 to 2019. The American Society of Clinical Oncology and Friends of Cancer Research have recommended that patients with treated or stable brain metastases should be routinely included in clinical trials and that those with active tumors should be considered for inclusion based on certain criteria.4


Approximately 30% of patients with EGFR-mutant NSCLC experience central nervous system (CNS) progression. The first generation of EGFR TKIs demonstrated poor ability to accumulate in the brain,1 but multiple lines of evidence suggest that the third-generation EGFR TKI osimertinib (Tagrisso) can cross the BBB and has significant activity in patients with brain metastases.

PET imaging studies have demonstrated BBB penetration of radiolabeled osimertinib in various animal models and healthy human volunteers.11,12 Similar findings were observed in patients with EGFR T790M–mutant NSCLC in the recent ODIN-BM study (NCT03463525), in which the drug achieved rapid, high, and widespread brain exposure.13

Osimertinib is approved for the frontline treatment of metastatic NSCLC and as adjuvant therapy for earlier-stage disease after resection for patients whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations; it also is approved as second-line therapy for metastatic NSCLC with EGFR T790M mutations.14 FLAURA (NCT02296125) and AURA3 (NCT02151981), the pivotal phase 3 trials in patients with metastatic disease, demonstrated a progression-free survival (PFS) benefit in the overall cohort, as well as in subgroups of patients both with and without CNS metastases.15,16

Meanwhile, a recent analysis of results from the ADAURA trial (NCT02511106), the pivotal study for osimertinib’s adjuvant indication, demonstrated that the drug cut the risk of CNS disease recurrence or death by 82% (HR, 0.18; 95% CI, 0.10-0.33), suggesting that osimertinib can protect patients against the development of CNS metastases when used in the adjuvant setting.17

Among other brain-penetrant EGFR TKIs in development, almonertinib (Ameile) is approved in China for the second-line treatment of EGFR T790M–mutant NSCLC.18 A recent study in mouse models found that almonertinib has a low affinity for BBB efflux transporters and that it readily penetrates the BBB.19 The phase 1/2 APOLLO study (NCT02981108) of almonertinib in patients with EGFR T790M–mutant NSCLC who had progressed after prior EGFR TKI therapy demonstrated promising activity in patients with CNS metastases; the CNS objective response rate (ORR) was 60.9% (95% CI, 38.5%-80.3%) and median PFS was 10.8 months (95% CI, 5.5-12.6).20

ALK-Positive CNS Disease

The first-generation ALK inhibitor crizotinib (Xalkori), which also inhibits ROS1 and MET, initially received accelerated approval for the treatment of locally advanced or metastatic ALK-positive NSCLC in 2011.21 Its indications have since expanded to include regular approvals for metastatic NSCLC tumors that test positive for ALK rearrangements or protein overexpression or for ROS1 fusions.22 A flurry of new and more potent ALK inhibitors have since been approved to address the resistance and disease progression that frequently occur.21,23

As with EGFR inhibitors, there has been an increasing focus on honing the ability of ALK inhibitors to cross the BBB and tackle brain metastases, which are frequently seen in patients with ALK-positive NSCLC at baseline and also have been observed at progression, including after ALK inhibitor therapy.23

Although ALK inhibitors have demonstrated efficacy in patients with ALK-positive NSCLC and brain metastases, the intracranial response rate varies among agents. Some investigators hypoth-esize that different drug mechanisms may play a role. Crizotinib and the second-generation ALK inhibitor ceritinib (Zykadia) are substrates for the efflux transporter P-glycoprotein (P-gp), which may hinder the accumulation of drugs in the brain, although intracranial ORRs exceeding 50% have been reported in cohorts of patients treated with these agents during clinical studies.23,24

Another second-generation ALK inhibitor, alec-tinib (Alecensa), which is not transported by P-gp, has been shown to accumulate in the brain in preclinical mouse models.25 In phase 3 trials, alectinib was found to substantially reduce the rate of progression in patients with CNS metastases compared with crizotinib. In the J-ALEX study (JapicCTI-132316), 1-year cumulative incidence rates favored alectinib over crizotinib for both CNS progression (5.9% vs 16.8%, respectively) and non-CNS progression (17.5% vs 38.4%, respectively). In ALEX (NCT02075840), CNS progression occurred in 18 patients (12%) on alec-tinib vs 68 patients (45%) on crizotinib (HR, 0.16; 95% CI, 0.10-0.28; P < .001). The 12-month cumula-tive incidence rates of CNS progression were 9.4% vs 41.4%, respectively.26

Brigatinib (Alunbrig) was approved in 2020 for the frontline treatment of ALK-positive metastatic NSCLC.27 In final results from the phase 3 ALTA-1L trial (NCT02737501), which was the basis for the approval, brigatinib reduced the risk of intracranial progression by 56% in all patients (HR, 0.44) and by 71% in patients with any brain metastases at baseline (HR, 0.29) compared with crizotinib.28

Lorlatinib (Lorbrena) is currently the only third-generation ALK inhibitor approved for the treatment of patients with ALK-positive NSCLC. It was specifically designed for enhanced BBB pene-tration, and imaging studies have demonstrated its rapid uptake and accumulation in the brain.29 In the recent CROWN trial (NCT03052608), lorlatinib was shown to elicit significantly higher intracranial response rates than crizotinib. The intracranial response rates in patients with base-line brain metastases were 82% (95% CI, 57%-96%) and 23% (95% CI, 5%-54%) in the lorlatinib and crizotinib groups, respectively.30

Ensartinib (X-396) is an investigational third-generation ALK inhibitor. Recently published results from the phase 3 eXalt3 trial (NCT02767804) demonstrated ensartinib’s superiority to crizotinib in patients with previously untreated ALK-positive NSCLC. Although only 11 patients with brain metastases at baseline were evaluated, the intracranial ORR was 63.6%, compared with 21.1% for crizotinib. Furthermore, significantly fewer ensartinib-treated patients went on to develop brain metastases at 12 months (4.2% vs 23.9% with crizotinib; HR, 0.32; 95% CI, 0.16-0.63; P = .001).31

Game-Changer Tucatinib

Breast cancer is the second most common cause of brain metastases after lung cancer, and CNS progression is particularly frequently associated with HER2-positive disease.32 HER2-targeted therapies have markedly improved the prognosis of patients with this subtype of cancer.

Investigators have thought that HER2-targeted antibody-drug conjugates (ADCs) were too large to cross the BBB. However, this concept may be challenged by the novel ADC fam-trastuzumab deruxtecan-nxki (Enhertu), which demonstrated a promising intracranial response rate of 83.3% (5 of 6 patients) in preliminary results from the phase 2 TUXEDO-1 trial (NCT04752059).33

Several small-molecule HER2 inhibitors with varying degrees of brain penetration are on the market. Most recently approved is the third-generation drug tucatinib. Tucatinib has not been directly shown to cross the BBB, but physiologically based pharmacokinetic modeling has predicted that it will be able to penetrate both the BTB and BBB and achieve pharmacologically active concentrations.34

Approval of tucatinib was largely based on results from the phase 2 HER2CLIMB trial (NCT02614794), in which the agent was combined with trastuzumab (Herceptin) and capecitabine for patients with previously treated metastatic HER2-positive breast cancer. Participants with brain metastases made up 48% of the cohort, and both this subgroup and the overall population displayed significantly higher 1-year PFS rates among patients who received the tucatinib combination compared with placebo plus trastuzumab and capecitabine.6,35

The FDA approval includes patients with brain metastases, making tucatinib the first targeted therapy specifically approved in this patient population. In a follow-up report, the tucatinib combination was also found to improve overall survival (OS)—the first drug to achieve this feat in HER2-positive patients with brain metastases—reducing the risk of death by 42% (HR, 0.58; 95% CI, 0.40-0.85; P = .005).6

BBB Disruption

Although significant advancements have been made in the development of small molecules that cross the BBB, the fact remains that almost all large drugs, including monoclonal antibodies and most chemotherapy agents, are unable to penetrate the protective barrier without assistance.

Numerous strategies have been tested to bypass the BBB, including convection-enhanced delivery, which uses a pressure gradient to facilitate direct delivery of the drug into the target tissue; intranasal delivery, which is thought to allow drug access to the brain through the olfactory and trigeminal neural pathways; and intra-arterial drug delivery, which involves administration of the drug directly into an artery in the proximity of the tumor. These methods have had limited success treating brain tumors to date, but clinical trials are ongoing.36

There also have been significant efforts to penetrate the BBB via transcytosis by encapsulating drugs in nanoparticles or conjugating them to ligands that trigger receptor-mediated uptake. A notable example of the latter approach is ANG1005, which consists of angiopep-2, a peptide that recognizes the LRP1 receptor on the surface of brain endothelial cells, conjugated to paclitaxel.37,38

In a phase 2 trial of ANG1005 in patients with breast cancer and brain metastases, a subset with leptomeningeal carcinomatosis (n = 28) had prolonged OS compared with historical controls. The ongoing phase 3 ANGLeD study (NCT03613181) is evaluating ANG1005 in patients with HER2-negative breast cancer who have newly diagnosed leptomeningeal carcinomatosis and previously treated brain metastases.38

Physical disruption of the BBB to temporarily increase its permeability is another strategy that is gaining in popularity. Several methods have been tested, but the use of FUS coupled with intravenously administered microbubbles, or US-BBBD, has shown the most promise.7,10

The acoustic pressure from the ultrasound causes the microbubbles to expand and contract, placing mechanical stress on the endothelial cells of the BBB and temporarily opening tight junctions between these cells, creating gaps through which drugs may pass in a process termed paracellular transport. The integrity of the BBB is typically fully restored within 24 hours after disruption.7

A major obstacle to delivering ultrasound to the brain is the thickness of the skull; the resulting ultrasound distortion necessitates the use of MRI or neuronavigation for safe guidance of the device. At least 3 specialized systems are in development for US-BBBD in the brain. ExAblate and NaviFUS are extracranial devices; the former consists of a hemispherical ultrasound helmet containing over 1000 transducers coupled with a magnetic resonance scanner, and the latter is a frameless neuronavigation-guided device. The SonoCloud system has an implantable ultrasound emitter, which is activated by a transcutaneous needle. Extracranial FUS can be radiologically guided by concurrent MRI or neuronavigation.39

US-BBBD has had significant success in preclinical studies, demonstrating the ability to safely, effectively, and transiently open the BBB to enhance the penetration of various drugs, thus improving antitumor efficacy.7

Early-phase clinical trials have begun, and promising preliminary data are emerging for both MRI- and neuronavigation-guided US-BBBD in patients with primary brain tumors and brain metastases.39-42 For example, in a first-in-human trial in 4 patients with HER2-positive breast cancer with brain metastases (NCT03714243), MRI-guided FUS safely enhanced the delivery of trastuzumab to the brain.42


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