Tucatinib Detectable in CSF of HER2+ Metastatic Breast Cancer With Leptomeningeal Disease


Tucatinib and ONT-993 were found to be detectable in the cerebrospinal fluid of all patients with leptomeningeal metastases from HER2-positive metastatic breast cancer who received treatment with tucatinib plus trastuzumab and capecitabine.

Debu Tripathy, MD

Debu Tripathy, MD

Tucatinib (Tukyska) and ONT-993 were found to be detectable in the cerebrospinal fluid (CSF) of all patients with leptomeningeal metastases from HER2-positive metastatic breast cancer who received treatment with tucatinib plus trastuzumab (Herceptin) and capecitabine (Xeloda), according to data from the phase 2 TBCRC049 trial (NCT03501979).1

This is the first documented evidence of tucatinib distribution into the CSF in this patient population, according to Debu Tripathy, MD, and this finding could have potential clinical implications for other cancer types with HER2 positivity.

Data from a pharmacokinetic analysis of the first 15 patients included in the investigator-initiated phase 2 trial showed that tucatinib and ONT-993 concentrations within the expected range and had high interindividual variability, following receipt of 300 mg of tucatinib. Moreover, CSF concentrations in cycle 1 ranged from 0.57 ng/mL to 12 ng/mL for tucatinib and from 0.28 ng/mL to 2.0 ng/mL for ONT-993. In cycle 2, these concentrations ranged from 0.94 ng/mL to 25 ng/mL for tucatinib and 0.31 ng/mL to 4.7 ng/mL for ONT-993.

Tucatinib concentrations in the CSF per time point following 300 mg of the agent were not found to significantly fluctuate with time. Moreover, these concentrations in the CSF were found to fall within a similar rang to plasma tucatinib concentrations over time. The median ratios for cycle 1 and cycle 2 were 0.60 (range, 0.17-2.0) and 0.83 (range, 0.19-2.1), respectively.

“This is a unique study, as we not only looked at the efficacy of this novel combination, which already has shown activity in [patients with] brain metastases, but we also performed pharmacokinetic studies, which are generally very difficult to do,” Tripathy said. “We wanted to see whether the drug enters the CSF, what its time course was in the blood, and what percentage of it makes it into the CSF.”

In an interview with OncLive®, Tripathy, professor and chairman in the Department of Breast Medical Oncology, of the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, further discussed the pharmacokinetic findings of tucatinib plus trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer with leptomeningeal disease and future directions for research.

OncLive®: What was the rationale for the TBCRC049 study?

Tripathy: Patients with metastatic HER2-positive breast cancer have a fairly high incidence of developing brain metastases. As many as 50% of these patients, over some course of their treatment, [will] experience [these] metastases. In some cases, this involves a particularly aggressive form of [disease] known as leptomeningeal disease; this involves the meninges and typically, one sees positive cancer cells in the CSF. This [disease] tends to have an even worse prognosis than intracranial metastases.

In the phase 2 HER2CLIMB trial [NCT02614794], which led to the approval of tucatinib, the addition of the agent to the backbone of capecitabine and trastuzumab was tested in patients with metastatic breast cancer. [The trial] even allowed [the enrollment of] patients with untreated brain metastases who did not receive local treatment but had minimal symptoms.

Overall, about half the patients in that study had brain metastases. The results did show that the addition of tucatinib improved progression-free survival [PFS] and overall survival, and it improved these outcomes particularly in those with brain metastases. [Additionally], responses were also observed in the patients who had untreated brain metastases. That study, as well as studies that had preceded it—the phase 1 study of tucatinib showed that patients with brain metastases [responded to treatment]—led to [the launch of the] TBCRC049 study to test [the regimen] in a smaller group of patients with leptomeningeal disease that is HER2 positive.

Could you expand on the design of this study?

The study design was to enroll patients with newly diagnosed leptomeningeal disease. These patients were diagnosed and confirmed, either by imaging or by CSF positivity, to have leptomeningeal involvement. Those patients underwent complete neuroimaging. They [also] underwent examination, both for standard-of-care, as well as research studies, including drug levels of their CSF. They were treated with capecitabine, tucatinib, and trastuzumab, according to the FDA-approved [label]. Patients received treatment if they did not have clinical or radiographic progression or intolerable adverse effects [to the] therapy.

What were the key takeaways from this study? Were there any that surprised you?

The study primarily looked at concentrations in the blood and in the CSF. [At the 2021 ASCO Annual Meeting] we reported [information on] the CSF concentrations. The results of the primary outcomes, which are overall response rate and time to progression, will be reported later, because patients are still being followed. 

We showed that patients did achieve [CSF] concentrations that were in the range of [0.57 ng/mL to 12 ng/mL with tucatinib], which is an active range; [tucatinib concentrations in the CSF] were maintained over time. These types of numbers really have not been described over time, with many drugs. The [CSF] concentrations range from 0.28 ng/mL to 4.7 ng/mL [for ONT-993, tucatinib’s predominate metabolite].

We also looked at the CSF to plasma ratios, and what percentage of the drug is getting through. The [median] CSF to plasma ratios in cycles 1 and 2, ranged from 0.60 ng/mL to 0.83 ng/mL, [respectively, with tucatinib and 0.66 ng/mL to 1.0 ng/mL, respectively, for ONT-993]; these [concentrations] did not really appear to fluctuate very much over time.

Do you believe that this study could be applied to other cancer types?

Yes. [Ongoing] studies [are being done] in other types of cancers that are HER2 positive. For example, gastric cancer is known to have a 20% to 25% positivity of HER2, and HER2 agents are approved [for use] in [patients with] gastric cancers. Now that we are doing next-generation sequencing on a broader number of patients, we are finding that either amplification or activating mutations can be found in HER2 in a very broad range of tumors. We are seeing [these alterations] in lung cancer, in colorectal cancer, bladder cancer. Even in [patients with] hormone receptor [HR]–positive, HER2-negative cancers, we are starting to see some who develop mutations in HER2—particularly those who have been exposed to endocrine therapy. That seems to be an escape mechanism for endocrine therapy.

We now test patients for mutations in HER2, because these are cases where the standard HER2 amplification and immunohistochemistry are negative; although it is not present in high amounts, the small amount that is present is mutated and turned on. We now know that these cases can respond to kinase inhibitors like neratinib [Nerlynx]. More recently, [it has been] shown that if [patients have] HR-positive [disease], we get better results if we combine [neratinib] with endocrine therapy like fulvestrant [Faslodex]. Most recently, [we saw even] better results if we combined [the agent] with trastuzumab.

As such, the way we approach multiple diverse tumors that are HER2 positive, either based on amplification or mutations, is changing. [Many of these] patients can stand to benefit from HER2-targeted agents. Similarly, for those who develop brain metastases from these tumors, they may benefit from the drugs that are known to cross the blood–brain barrier.

What are the next steps for research with this combination?

We want to complete this study so we can define what tucatinib-containing regimens can do for [patients with] leptomeningeal disease. Other studies [are] looking at [how these combinations can help those with] brain metastases, as well.

We are looking at different ways to treat [patients with] HER2-positive breast cancers based on mutations, using agents like antibody-drug conjugates [ADCs]. That is another area where we've seen major improvements in the treatment of HER2-positive disease. For example, the ADC known as trastuzumab deruxtecan [Enhertu], has shown dramatic results—not only in [those with] HER2-positive disease, but [also in those] with HER2-low disease who are technically HER2 negative but express it at a level of 1 to 2+, but without amplification of the gene. This is a very exciting area where we can treat HER2-low disease. Some patients with central nervous system disease have responded to this agent, even though it is an antibody-based agent; [these agents] are not thought to penetrate the blood­–brain barrier very well. Regardless, we are seeing responses [with this approach]. Several studies are now looking at this ADC, as well as others, [in the treatment of those with] HER2-positive brain metastases.

One of the big controversies in the field, because patients with advanced HER2-positive breast cancer develop brain metastases at such a high rate, is whether they should be screened automatically for brain metastases if they are not symptomatic. We do not typically obtain a brain MRI unless we see symptoms, and we do not even know if it is helpful to pick patients up early before they need treatment, because it is possible that some may do fine with systemic therapy. Once we know they have brain metastases, we monitor them, and we treat everything that shows up with stereotactic radiation, or even whole brain radiation. We may be over treating these patients.

However, on the other hand, it is very disturbing when you have a patient who has advanced breast cancer, and they present with a seizure as their first manifestation of a brain metastases. Many of them ask whether they should have had their brain [screened] and we say no, because that is not the standard of care. It really begs the question of whether we should be doing it. Some ongoing pilot studies are [exploring] going ahead and getting a brain MRI and then following the outcomes of these patients so we can better characterize this. It may very well be that these kinds of studies will lead to a change in this paradigm.


  1. Stringer-Reasor E, O’Brien B, Topletz-Erickson A, et al. S Pharmacokinetic (PK) analyses in CSF and plasma from TBCRC049, an ongoing trial to assess the safety and efficacy of the combination of tucatinib, trastuzumab and capecitabine for the treatment of leptomeningeal metastasis (LM) in HER2 positive breast cancer. J Clin Oncol. 2021;39(suppl 15):1044. doi:10.1200/JCO.2021.39.15_suppl.1044
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