September 2020 Edition Vol.11, Issue 9

Therapeutic Approach to Brain Metastases Might Undergo Fundamental Change

By Ted Bosworth

Four major takeaways stand out from the recently held 2020 Virtual Conference on Brain Metastases hosted by the Society of NeuroOncology. One is that actionable mutations of brain metastases and primary tumors are not necessarily the same, initiating a potential reorientation toward individualized therapy. Another, drawn from a substudy of a phase 3 trial, is that the overall survival (OS) benefit from a recently approved HER2-targeted therapy for metastatic breast cancer is at least as good in those with brain metastases as in those with extracranial metastatic disease but no brain metastases.

A third, is that long-term cognitive outcomes are worse following whole brain radiotherapy (WBRT) than stereotactic radiosurgery (STS) for brain metastases even if long-term impact on quality of life is more mixed. Finally, new work shows that circulating tumor cells (CTC) in the cerebrospinal fluid (CSF) of patients with brain metastases correlate with survival.

Genetic Characterization Might Profoundly Alter Management of Brain Metastases

Several independent groups have shown that the genetic evolution of brain metastases and primary tumors is different, but now there is emerging evidence that it is clinically relevant. A small pilot study showing intracranial response and clinical benefit from therapy individualized to driver mutations of brain metastases has provided the basis for a major new initiative.

“Because of the success of this [pilot] study, we have now initiated a national biomarker-driven trial in brain metastases. It is a trial that is up and running,” according to Priscilla K. Brastianos, MD, Director of the Central Nervous System Metastasis Program, Massachusetts General Hospital, Boston.

This phase 2 national trial with funding from the National Cancer Institute is evaluating genetic testing as a guide to brain metastasis treatment selection. Dr. Brastianos, the chair, said more than 300 institutions are participating.

Primary tumors and their metastases share common genetic ancestry, but there are now several published papers showing that these have a “branched evolution,” meaning that these tumors and their primaries evolve independently, according to Dr. Brastianos. With evolution, the therapy most effective for one will not necessarily be the most effective for the other.

“More than 50% of brain metastases have different drivers than the primary tumor,” said Dr. Brastianos, citing her work and the work of others. It was this observation that led to a pilot study of a therapy personalized for driver mutations of brain metastases in 15 heavily pretreated patients with a mix of primary tumor histologies. Eight achieved intracranial benefit, defined as complete response, partial response, or stable disease, meeting the primary endpoint.

In the national trial, enrollment is open to patients with brain and extracranial site tissue for genomic sequencing. Actionable mutations are being treated with targeted therapies, such as inhibitors of mutations of the CDK, P13K, and NTRK/ROS1 genes. The trial has the potential to profoundly alter management of brain metastases.

If the biomarker trial supports an individualized approach, genetic characterization of brain metastases is likely to become fundamental to treatment choice. If true, Dr. Brastianos expressed hope that liquid biopsy of the CSF will prove to be a viable alternative to craniotomies.

Substudy of HER2CLIMB Trial Confirms Major Benefit Against Brain Metastases

Tucatinib, which was recently approved for treatment of metastatic breast cancer, is associated with an overall survival (OS) benefit in patients with active brain metastases, according to an exploratory subgroup analysis of the HER2CLIMB trial. Results from the phase 3 trial provided the basis for the tucatinib approval in April of this year (Murthy RK et al. N Engl J Med 2020;382:597-609).

In patients with brain metastases, the addition of tucatinib rather than placebo to the combination of trastuzumab and capecitabine, was associated with a 42% reduction in the risk of death (HR 0.58; P=0.005). For progression-free survival (PFS), which was the primary endpoint, tucatinib was associated with a 68% relative advantage (HR 0.32; P<0.0001). The OS and PFS benefits for tucatinib relative to placebo in the whole study population were 34% (P=0.005) and 46% (P<0.001), respectively.

The HER2CLIMB trial enrolled patients with HER2-positive metastatic breast cancer previously treated with trastuzumab or another monoclonal antibody targeted at HER2. Patients were randomized to tucatinib, a tyrosine kinase inhibitor (TKI) highly selective for HER2, or placebo in combination with trastuzumab and capecitabine. Approximately 46% had brain metastases at enrollment.

In the subgroup of patients with brain metastases, “tucatinib in combination with trastuzumab and capecitabine doubled the intracranial objective response rate, reduced the risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half,” reported Nancy U. Lin, MD, Clinical Director, Breast Oncology Center, Dana-Farber Cancer Institute, Boston.

For those with active brain metastases at enrollment, PFS in the central nervous system (CNS), which was measured with RECIST 1.1 criteria, increased more than two-fold (9.5 vs. 4.1 months; P<0.0001) in those treated with tucatinib rather than placebo.

In those with stable brain metastases at entry, the relative PFS advantage for CNS disease was even greater (13.9 vs. 5.6 months; P=0.002), but the OS advantage, although numerically greater (15.7 vs. 13.6 months; P=0.7) did not reach statistical significance.

As previously reported, diarrhea and elevated liver enzymes were more common in those who received tucatinib than placebo but were largely low-grade events. Only 6% of patients discontinued tucatinib due to adverse events.

Despite the recent evidence that brain metastases evolve differently than primary tumors, Dr. Lin explained that the efficacy of tucatinib is consistent with a study that compared the status of breast cancer biomarkers, including HER2 status, in brain metastases versus primary breast cancers.

The investigator “found that HER2 loss is relatively uncommon between the primary and the brain metastasis, although sometimes he did see it,” Dr. Lin said.

For Preservation of Cognition, Stereotactic Radiotherapy Beats Whole Brain Radiotherapy

Stereotactic radiotherapy (SRS) is substantially better at preserving long-term cognitive function than whole brain radiotherapy (WBRT), according to pooled data from two similarly designed trials comparing these modalities for treatment of patients with a limited number of brain metastases.

In this analysis, characterized as the first large prospective pooled study to compare SRS and WBRT for cognitive function over an extended period, there was a linear decreasing performance trend over time in only two of the six cognitive tests among SRS-treated patients versus five of the six tests in those treated with WBRT, according to Joshua D. Palmer, MD, a radiation oncologist at the Wexner Medical School, Ohio State University, Columbus.

These cognitive outcome data were drawn from two previously published multicenter trials that compared SRS to WBRT for the control of brain metastases. Both of the studies, NCCTG N0574 and NCCTG N107C, were conducted by the Alliance for Clinical Trials in Oncology. Each enrolled about 200 patients with up to three brain metastases. The cognitive data presented by Dr. Palmer was in a group of 88 long-term survivors. The median followup in this group was 24 months.

Cognitive deterioration on any given test was defined as more than one standard deviation (SD) in the score from baseline, but investigators looked at multiple endpoints, including the number of tests on which deterioration was seen and the proportion of patients with 2 or more SD decline on one or more tests. For all cognitive outcomes, SRS was favored significantly or numerically.

As a second objective of this analysis, Dr. Palmer and his coinvestigators evaluated whether a two SD decline predicted a worse quality of life (QOL). Measured with the brains-specific version of the Functional Assessment of Cancer Therapy (FACT-Br) QOL Tool, the answer was yes for overall QOL and the domain of functional well being.

These data “make it more meaningful to try to spare a cognitive impact that can be severe and potentially not treatable because it can impact these patients long-term,” Dr. Palmer said.

Circulating Tumor Cells in CSF Predict Survival in Patients with Brain Metastases

When quantified in the CSF, circulating tumor cells (CTCs) predict survival in newly diagnosed leptomeningeal metastases (LM) from primary solid tumors, according to a retrospective review of CTC testing of samples collected from patients with brain metastases.

Based on findings from 101 patients with newly diagnosed LM, there is a continuous relationship between increased number of CTCs and reduced survival, with risk of death increasing by 0.4% (HR 1.004; 95% CI, 1.001 – 1.007; P=0.02) for each CTC, according to Maria Diaz, MD, Memorial Sloan Kettering Cancer Center, New York.

With a cutoff of 61 CTCs per 3 ml of CSF, the risk of death was twice as greater for those with more CTCs when compared to those with fewer (HR 2.09; P=0.02).

The potential for the evolution of CTCs over time to reveal change in prognosis could not be determined in this study, which only had values for one point in time. Prospective studies to verify these results will explore this application. Conceivably, CTCs might prove to be an important biomarker not only for prognosis but also for other clinical applications including a determination of response to therapy.

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