Tucatinib-Based Regimen Improves Target Deficits, QOL in HER2+ Breast Cancer With Leptomeningeal Metastasis

Key Takeaways

  • Tucatinib, trastuzumab, and capecitabine improved intracranial responses, overall survival, and quality of life in HER2-positive metastatic breast cancer with leptomeningeal metastasis.
  • 58% of patients with baseline neurologic deficits showed improvement, and all response-eligible patients experienced clinical benefit.
Barbara Jane O'Brien, MD

Barbara Jane O'Brien, MD

Treatment with a systemic regimen comprising tucatinib (Tukysa), trastuzumab (Herceptin), and capecitabine (Xeloda) elicited intracranial responses, prolonged overall survival (OS), and improved patient-reported quality of life (QOL) in patients with HER2-positive metastatic breast cancer with leptomeningeal metastasis, including those with target deficits at baseline, according to preliminary data from the phase 2 TBCRC049 study (NCT03501979) presented during the 2024 ASCO Annual Meeting.1

Among evaluable patients with target neurologic deficits at baseline (n = 12), 58% experienced an improvement of deficits, and 5 demonstrated stable target deficits as their best response. Six of the 7 patients with improved target deficits experienced this at their first restaging. Notably, no patients received steroids in the interval.

Furthermore all 13 response-eligible patients experienced clinical benefit with the regimen, including 8 who achieved stable disease and 4 partial responses (PRs), including 1 PR at cycle 3 that became a complete response (CR) by cycle 9. The leptomeningeal objective response rate (ORR) per composite criteria was 38%.

Overall survival was also prolonged in this population, with 4 patients remaining alive at the time of last follow-up, which was July 21, 2021. Further assessment of patient-reported outcomes and QOL showed that patients’ mean MD Anderson Symptom Inventory (MDASI) and Linear analogue self-assessment (LASA) scores improved over time, which indicates an increase in QOL.

“This is the first prospective study to demonstrate the combination of intracranial response, improved symptoms, improved QOL, and extended survival from a systemic regimen in patients with leptomeningeal [disease] from breast cancer,” lead study author Barbara Jane O’Brien, MD, an associate professor of Neuro-Oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas, stated in a presentation of the data. “These data support systemic therapy as an initial approach in leptomeningeal [disease] from HER2-positive breast cancer.”

Tucatinib plus trastuzumab and capecitabine gained FDA approval in April 2020 for patients with HER2-positive breast cancer, including those with brain metastases, who were previously exposed to at least 1 HER2-based regimen in the metastatic setting. The investigator-initiated, nonrandomized TBCRC049 study sought to assess this tucatinib-based regimen in patients with leptomeningeal metastasis from HER2-positive breast cancer.

Previously reported data from the study demonstrated therapeutic levels of tucatinib and ONT-993 in the cerebrospinal fluid of all patients who received the combination, and the regimen had a safety profile consistent with that observed in prior tucatinib studies. Additionally, the combination led to a median OS of 10 months (95% CI, 4.1-not reached) and median time to central nervous system (CNS) progression was 6.9 months (95% CI, 2.3-13.8). Following the FDA approval of this tucatinib-based regimen, the study was closed with 17 patients due to a lack of accrual. The current analysis features response data from the trial.

Of the 17 patients enrolled, 47% had abnormal CSF cytology, and 88% had symptoms from leptomeningeal metastasis. All patients had evidence of leptomeningeal metastasis according to MRI, 82% of whom also displayed brain metastases; 65% had received prior treatment for brain metastases. The median number of 3-week treatment cycles administered to patients was 5 (range, 2-27). Leptomeningeal composite ORR and patient-reported outcomes and QOL were all assessed, and up to 4 target neurologic deficits were identified per patient.

Response assessment consisted of a neurologic clinical exam, CSF pathology, and MRI neuroaxis imaging using standardized scorecards. To qualify for a leptomeningeal composite response, patients must have displayed improved or stable target deficits according to neurologic clinical evaluation, negative CSF cytology following a positive result at baseline, and radiologic PR or CR according to CNS imaging. Neurologic/clinical defined progression required a worsening of target deficits, negative or positive CSF cytology, and stable CNS imaging. Radiologic progression was defined as stable or worsened target deficits, negative or positive CNS cytology, and progressive disease.

In the overall population, 4 patients were not deemed response evaluable due to study discontinuation prior to the first restaging. Reasons for discontinuation included toxicities (n = 1), patient choice (n = 1), or progressive disease (n = 2). At the time of last follow-up, 12 patients discontinued treatment due to leptomeningeal metastasis progression, 7 of whom also experienced CNS progression. Three patients discontinued treatment due to systemic progression.

All participants completed the majority of MDASI and LASA questionnaires at all time points required. O’Brien explained that lower MDASI scores indicated improved symptom burden, and higher LASA scores indicated better QOL.

Key study limitations include no central review of imaging findings and a small number of participants. Additionally, no validated composite response assessment in leptomeningeal metastasis, although proposed Response Assessment in Neuro-Oncology–Leptomeningeal criteria were adapted.

Disclosures: Dr O’Brien reports serving in a consulting or advisory role for Plus Therapeutics and receiving institutional research funding from EMD Serono and Kinarta.


O’Brien BJ, Murthy RM, Berry DA, et al. Tucatinib-trastuzumab-capecitabine for treatment of leptomeningeal metastasis in HER2+ breast cancer: TBCRC049 phase 2 study results. J Clin Oncol. 2024;42(16):2018. doi:10.1200/JCO.2024.42.16_suppl.2018

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