Tucatinib, Trastuzumab, and Capecitabine May Be Efficacious in HER2+ BC With Leptomeningeal Metastasis

Erica Stringer-Reasor, MD

While the combination of tucatinib (Tukysa), trastuzumab (Herceptin), and capecitabine (Xeloda) is FDA approved for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases who have received one or more prior anti-HER2-based regimens in the metastatic setting, it has never been study as treatment of patients with leptomeningeal metastasis. In fact, many studies take steps to exclude patients with leptomeningeal metastasis due to the aggressive nature of the disease.¹

Currently, a phase 2 study (NCT03501979) is underway in order to determine the pharmacokinetics of the triplet combination in patients with HER2-positive breast cancer with leptomeningeal metastasis. The study has an estimated enrollment of 30 patients and a primary end point of overall survival. Secondary end points include the number of adverse events, progression-free survival, object response, clinical benefit rate, symptom burden, and quality of life assessment.²

An interim analysis of 15 patients found tucatinib and its parent drug ONT-993 had plasma concentrations consistent with previous studies while also exhibiting high interindividual variability. Both tucatinib and ONT-993 were detectable in the CFS within 2 hours after tucatinib administration, with concentrations ranging from 0.57 to 25 ng/mL for and 0.28 to 4.7 ng/mL for ONT-993.

In an interview with Targeted Oncology™, Erica Stringer-Reasor, MD, an assistant professor of medicine at the University of Alabama at Birmingham, discusses the study in more detail and how this newly approved triplet combination may improve survival for patients living with HER2-positive breast cancer with central nervous system (CNS) metastases.

TARGETED ONCOLOGY™: Can you provide an overview of the data you presented at ASCO this year?

STRINGER-REASOR: During ASCO this year, myself and my collaborators presented a phase 2 study evaluating the efficacy of the combination of tucatinib, trastuzumab, and capecitabine in the treatment of HER2-positive metastatic breast cancer. So, in this abstract, specifically, we will discuss the pharmacokinetic analysis of the first 15 patients.

What was the design and primary objective of your study?

Leptomeningeal metastasis is a rare but aggressive form of breast cancer with very limited treatment options. There are not many randomized studies or single arm studies evaluating this purely due to the rareness of this disease. Although we definitely know that as we treat patients with HER2-targeted therapies, it will treat their body systemically. But eventually, they will have a central nervous system [CNS] relapse. We thought it would be important to

investigate this in a small cohort of patients in a combination that was recently approved by the FDA for metastatic breast cancer, as well as specifically in patients diagnosed with brain metastases. Again, this combination has not been evaluated in leptomeningeal disease.

What were your results and did anything stand out to you?

The combination of tucatinib, trastuzumab and capecitabine has been recently FDA approved for the treatment of advanced metastatic HER2-positive breast cancer, in addition to patients diagnosed with brain metastases. But there's been no study to really evaluate this combination in leptomeningeal disease. In fact, in most clinical trials, leptomeningeal disease is often excluded from studies due to its aggressive nature. In this study, we evaluated the first 15 patients and assess the pharmacokinetics in the CSL as well as in the plasma. And what we found is that tucatinib and its parent drug, ONT-993 were detected in both the CSF and were proportional to levels in the plasma. So, to our knowledge, this is the first study to evaluate tucatinib and its parent metabolite in the CSF.

Currently, we are at a total enrollment of 18 patients, which we hope to accrue 30 patients to this study. And we hope to evaluate the efficacy and safety of this combination at a later date and report it was all patients have been accrued.

What are the next steps after you hit your enrollment goal?

One of the future directions of research, utilizing this interest in molecules and drugs, very similar to this would be to bring it to the earlier stages. We know that patients, again, at higher risk of brain metastases, and we suspect, again, is because there is so many drugs that are very active in the body, but do not penetrate the CNS. And so therefore, I'm trying to look at studies that could bring this to patients in the earliest days, so that they do not ever have CNS disease.

How would this combination fill an unmet need in this patient population?

This combination would definitely fill an unmet need. Again, right now, for most patients, their options may be surgery and radiation, or some type of radiotherapy. But the median progression free survival is about 4 months in those patients. And we want to be able to evaluate the efficacy of this combination to not only preserve the quality of life but prolong life as well. So again, I hope that we are able to present that data at a later time.

_REFERENCES:

_{1. 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(15):1044 doi: 10.1200/JCO.2021.39.15_suppl.1044}

_{2. Tucatinib, trastuzumab, and capecitabine for the treatment of HER2+ LMD. ClinicalTrials.gov. Accessed August 18, 2021. https://bit.ly/3xSlx1C.}