Novel therapies, technologies give ‘hope for the future’ to those with brain metastases
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An estimated 10% to 40% of patients with solid tumors develop brain metastases.
Incidence — which is highest among those with primary melanoma or lung, breast, colon or kidney cancers — has increased over time due to improvements in systemic treatments, which have prolonged survival for many patients with cancer.
Only a couple decades ago, brain metastases equated to an almost-certain death sentence, with survival far more often measured in weeks or months than years.
However, advances in genomic profiling and the development of targeted therapies dramatically transformed the prognosis for many patients, according to Manmeet S. Ahluwalia, MD, MBA, FASCO, chief of medical oncology, chief scientific officer and deputy director at Miami Cancer Institute, part of Baptist Health South Florida.
"Until recently, outcomes of patients with brain metastases were dismal, with average survival of 6 months to 9 months," Ahluwalia — a Healio | HemOnc Today Editorial Board Member — said in an interview. “Now, thanks to the use of targeted therapies, patients with EGFR-mutant lung cancer brain metastases live approximately 24 months, and those with ALK translocation lung cancer brain metastases have a reported average survival of around 48 to 60 months."
Healio spoke with several neuro-oncologists and researchers about advances in treatment of brain metastases, their effects on survival and quality of life, novel approaches under investigation to further improve outcomes and efforts to overcome long-perceived therapeutic barriers.
Penetrating the fortress
Increased incidence of brain metastases over the past decade is an unfortunate consequence of some very significant treatment advances, according to Ashley L. Sumrall, MD, FACP, neuro-oncologist and clinical assistant professor at Levine Cancer Institute at Atrium Health.
“As people live longer with these better therapies, they’re developing spread to the brain,” Sumrall — a Healio | HemOnc Today Editorial Board member and Healio Women in Oncology Peer Perspective Board member — said in an interview.
However, much like oncology in general, outcomes for this sizable subgroup of patients with cancer continue to improve.
“We used to think that brain metastases were the end,” Sumrall said. “Now we know that, depending on the tumor of origin, a person can live for years.”
Research into brain metastases historically had been limited primarily to retrospective studies due to restrictive clinical trial eligibility criteria, but that also is changing.
“An increasing number of clinical trials allow [individuals with] brain metastases or are developed [specifically] for these patients,” Sumrall said. “There’s been this push to reconsider how we [design] our clinical trials and to make them more inclusive. For years, patients with brain metastases were excluded because they were considered high risk. Now there is increased enthusiasm to open those studies, thereby offering more treatment options for these patients.”
Still, the knowledge base about what makes brain metastases so heterogeneous remains in its infancy, Sumrall said. As specialists learn more about their biology, evidence supports the theory that they are much more complicated to treat than primary tumors.
First, treatment must effectively target metastases without damaging healthy — and extremely sensitive — surrounding tissue.
Second, therapeutics must be able to cross the blood-brain barrier with a sufficiently high concentration to deliver an effective antitumor payload.
The blood-brain barrier long had been considered “an impenetrable fortress,” Sumrall said.
“That thinking has since proven false,” she said. “It more resembles a leaky sieve that can be disrupted in some manner by other treatments — and the tumors themselves.”
Research has shown large-molecule agents — including monoclonal antibodies — can penetrate the blood-brain barrier.
“We still don’t understand how,” Sumrall said. “It’s like driving a giant truck through a tiny gate. It shouldn't get in, but it does. As we continue to gain experience, we must expand our thinking and consider this barrier as something that’s different depending on the patient or the tumor type.”
The need to cross the blood-brain barrier to treat brain metastases makes them unique — and more challenging — than treating solid tumors in other parts of the body, such as the liver or lung.
This has led to a “concentrated effort” to develop therapies that can permeate the blood-brain barrier — or at least disrupt it — to deliver more effective treatments, Ahluwalia said.
‘Genetic divergence’
Even if therapies cross the blood-brain barrier, other formidable challenges remain.
One is the frequent inability to biopsy tumor tissue in the brain.
The other is the potential for “genetic divergence,” according to Priscilla K. Brastianos, MD, director of the Central Nervous System Metastasis Center at Mass General Cancer Center and associate professor of medicine at Harvard Medical School.
In 2015, Brastianos led a research team that published findings in Cancer Discovery demonstrating that brain metastases can have different genetic alterations than their primary tumors.
Their research suggested new genomic alterations may arise in up to half of brain metastases cases.
“This is an important additional challenge when it comes to treating patients with brain metastases,” Brastianos said. “They might not have the same molecular targets that tumors outside of the brain have.”
Decisions about targeted therapies for individuals with brain metastases often are based on biopsies of primary tumors, Brastianos said. Meanwhile, the actionable genetic alterations present in brain metastases may not be detected during testing of primary tumors, meaning some patients may not receive appropriately targeted therapy directed toward the genetic alterations in the brain.
The results Brastianos and colleagues published fundamentally shifted the way clinicians think about how brain metastases should be treated, Sumrall said.
“A lot of new research has spawned from her group’s findings, and we are starting to write new studies based on the information,” Sumrall said. “We are finally starting to understand why some of these tumors spread to the brain, and we hope figuring out the ‘why’ can open a door on how to target them more effectively.”
‘A huge shift’
The landscape of clinical research into brain metastases has changed dramatically in recent years, according to Carey K. Anders, MD, professor of medicine and chief of the division of medical oncology at Duke University School of Medicine and medical director of the Duke Center for Brain and Spine Metastasis.
During her medical training, patients with active or history of brain metastases were excluded from trials.
“There’s been a huge shift in terms of inclusion of patients with brain metastases in clinical trials, which I think is an advance in and of itself,” Anders told Healio. “If we don’t try these novel agents early on for patients with [central nervous system] disease, we won’t know if they work. So far, we have been surprised by what we found.”
Perhaps the biggest surprise has been the effectiveness of antibody-drug conjugates, Anders said.
Antibody-drug conjugates have an established track record for treating both solid tumors and hematologic malignancies using molecular targeting. Newer therapies have successfully balanced delivery of effective cancer-killing payloads with fewer toxicities.
“Many of us thought that antibodies — being large, bulky molecules — would never be able to traverse the blood-brain barrier,” Anders said. “That may be true of the antibody but, when you have a very potent payload and a high drug-to-antibody ratio, you can actually see really nice responses in the brain to antibody-drug conjugates.”
Anticancer therapies appear to work better in the CNS when they have an actionable molecular target, Anders said. This has been observed in studies that evaluated small-molecule inhibitors to target EGFR in lung cancer metastases or BRAF alterations in melanoma metastases.
As research emerged about the efficacy of ado-trastuzumab emtansine (Kadcyla, Genentech) for treating brain metastases from HER2-positive breast cancer, investigators conducted retrospective studies to identify whether other antibody-drug conjugates may be able to play a role in targeted treatment of brain metastases.
“Over time, we had the feeling that these drugs might be much more effective than was assumed, so we tried to convince partners to work with us on prospective studies,” Matthias Preusser, MD, head of the division of clinical oncology at Medical University of Vienna, told Healio. “We were successful convincing some companies to work with us and sponsor prospective clinical trials, and that’s how we ended up with the TUXEDO program.”
The single-arm phase 2 TUXEDO-1 trial — for which Preusser served as a principal investigator — assessed the HER2-directed antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) for treatment of adults with HER2-positive breast cancer with either newly diagnosed untreated brain metastases or brain metastases that progressed after prior local therapy.
Fifteen patients received at least one dose of fam-trastuzumab deruxtecan-nxki. Median follow-up was 12 months.
Results published last year in Nature Medicine showed the study met its predetermined primary efficacy outcome, with an overall intracranial response rate of 73.3% (95% CI, 48.1–89.1). Researchers reported median PFS of 14 months. Median OS had not been reached.
“The results challenge the old dogma that antibody therapies would not impact CNS metastasis,” Preusser said. “We saw very high response rates with these large complex molecules, when everyone assumed they would not get into the tumors at all. Seventy-three percent of brain metastases objectively shrank, which was much higher than our expectation of 40%, so the study drug conferred quite a substantial benefit.”
Study participants also exhibited stable neurocognitive function during the treatment period. Preusser called this encouraging because other standard treatments — including radiation therapy — typically result in neurocognitive decline.
“It’s an indication in the right direction,” he said. “With drug treatment, it may be possible to preserve patients’ quality of life and neurocognitive function.”
More TUXEDO trials are planned to evaluate the effectiveness of antibody-drug conjugates for brain metastases. TUXEDO-2 will focus on individuals with triple-negative breast cancer, TUXEDO-3 will include patients with a variety of solid tumors and TUXEDO-4 will enroll patients with HER2-low breast cancer.
Role of immunotherapy
Although the blood-brain barrier is a complex system to negotiate, potent anticancer agents already are available to help treat brain metastases, Preusser said. The challenge is identifying the ones that confer the most benefit and learning how to deliver them in the most effective manner.
“Many thought immunotherapy would not work in the brain because of how the immune system in the brain works and the blood-brain barrier, but it appears that immune checkpoint inhibitors work in brain metastases," Preusser said. “If the drug is an active one — in my experience — it will also work in the brain.”
At this year’s ASCO Annual Meeting, Brastianos presented results of a single-arm phase 2 study that evaluated the PD-1 inhibitor pembrolizumab (Keytruda, Merck) for adults with brain metastases.
"[Previous research] suggests that the brain metastasis tumor microenvironment is more immunosuppressive [than] primary tumors or extracranial metastases,” Brastianos said. “For that reason, we wanted to explore immune-based strategies that augment T-cell cytotoxicity within brain metastases.”
The results — also published in Nature Medicine — showed the study met its primary endpoint with an intracranial benefit rate of 42.1% (90% CI, 31-54). Researchers reported median OS of 8 months (90% CI, 5.5-8.7 months), with seven patients (12.3%) surviving longer than 2 years.
"There was no good standard of care for many of the patients enrolled in this study because they had recurrent disease, so an intracranial benefit rate of 42% is encouraging for this patient population for whom there is no FDA-approved treatment,” Brastianos said. “Our results suggest that pembrolizumab does have promising activity in a subset of patients with brain metastases, although more research is still needed.”
Her lab’s next steps are to explore biomarkers that may indicate which patients may respond favorably to immunotherapy within the brain, and to examine immunotherapy in combination with other agents.
"Novel medical therapies are truly making an impact on this patient population,” Brastianos said. “Targeted therapies, as well as immunotherapy, are playing an increasingly important role for patients with brain metastases.”
The LIMITLESS approach
With evidence that certain drugs can cross the blood-brain barrier, researchers have concentrated on making those drugs more effective within the CNS environment.
Use of focused ultrasound to disrupt the blood-brain barrier could prove transformative for its ability to enhance the amount of large-molecule antibody-drug conjugate or immunotherapy drug that can be delivered to the brain, Ahluwalia said.
He is principal investigator for the randomized LIMITLESS study, in which researchers will use focused ultrasound to open the blood-brain barrier to enable higher concentrations of an immunotherapy drug to enter the brain tumor tissue.
The study uses the Exablate Neuro (Insightec) focused ultrasound device to deliver circulating microbubbles — ultrasound contrast agents — that oscillate within the ultrasound field with the aim of disrupting the blood-brain barrier.
"The blood-brain barrier limits the efficacy of systemic therapies for brain metastases, and blood-brain barrier disruption has been demonstrated in preclinical models to improve systemic drug delivery for brain metastases," Ahluwalia said. "Low-intensity focused ultrasound results in noninvasive blood-brain barrier disruption synergistically with IV administered microbubble oscillators."
A prior single-arm prospective study established the safety and feasibility of using focused ultrasound to target intracranial metastases with simultaneously administered trastuzumab, Ahluwalia said.
“Preliminary results for four [patients who] underwent a combined total of 20 Exablate procedures demonstrated successful blood-brain barrier opening,” he said. “Trastuzumab delivery was achieved in all targets and was associated with clinical benefit in these patients.”
The LIMITLESS study has an initial planned enrollment of 20 participants with non-small cell lung cancer brain metastases. Researchers will randomly assign patients to pembrolizumab alone or with focused ultrasound.
Investigators recently treated the first five patients and they observed no safety issues, Ahluwalia said.
No longer ‘a dealbreaker’
The blood-brain barrier remains an important consideration in treatment of brain metastases.
However, the feasibility and effectiveness of novel therapeutic approaches suggest it may not be the tremendous obstacle it has long been considered, according to the experts with whom Healio spoke.
Innovative targeted agents have proven potent enough to penetrate the blood-brain barrier, and early clinical trials have yielded promising results, Ahluwalia said.
"A noninvasive method to disrupt the blood-brain barrier can be the game changer [for] these patients and hence the interest in focused ultrasound," Ahluwalia said. "Multimodality novel approaches will further transform outcomes for patients with brain metastases in the coming decade. Given these unique methods of treatment delivery, perhaps the blood-brain barrier is not as big an issue as previously believed.”
Preusser agreed.
“I don’t think the blood-brain barrier is a dealbreaker,” he said. “I think it’s a complexity that needs to be considered, but it’s not prohibitive.”
Researchers often simply blame the blood-brain barrier when a new approach fails to show benefit in clinical trials, Preusser said.
“I believe that — most of the time — if a drug doesn’t work, it is the drug’s fault because it’s just not active enough,” Preusser said.
“We are witnessing a substantial shift in how some patients with brain metastases are being treated,” he added. “Brain metastases still have a poor prognosis but, based on molecular insights and the availability of new drugs, we are making some progress. Antibody-drug conjugates, immunotherapies, tyrosine kinase inhibitors — they all hold great promise.”
Brastianos also expressed confidence about improving outcomes for individuals who develop brain metastases, despite the additional layers of complexity.
“Yes, the blood-brain barrier does offer challenges to drug delivery,” she said. “However, as a field, we have been able to make huge leaps forward in this area.”
Much work remains given most individuals who develop brain metastases eventually die of their disease, Brastianos said. However, the progress is reason for optimism.
“We are seeing significant improvement in survival times and outcomes using novel therapies and technologies,” Brastianos said. “There is hope for the future.”
References:
- Bartsch R, et al. Nat Med. 2022;doi:10.1038/s41591-022-01935-8.
- Brastianos PK, et al. Cancer Discov. 2015;doi:10.1158/2159-8290.CD-15-0369.
- Brastianos PK, et al. Nat Med. 2023;doi:10.1038/s41591-023-02392-7.
- Brastianos PK, et al. Abstract 2006. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
- Lamba N, et al. Neuro Oncol. 2021;doi:10.1093/neuonc/noab101.
For more information:
Manmeet S. Ahluwalia, MD, MBA, FASCO, can be reached at manmeeta@baptisthealth.net.
Carey K. Anders, MD, can be reached at carey.anders@duke.edu.
Priscilla K. Brastianos, MD, can be reached at pbrastianos@mgh.harvard.edu.
Matthias Preusser, MD, PhD, can be reached at matthias.preusser@meduniwien.ac.at.
Ashley L. Sumrall, MD, FACP, can be reached at ashley.sumrall@atriumhealth.org.
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