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----Tucatinib-based treatment regimen improves target deficits and quality of life in HER2+ breast cancer with leptomeningeal metastases

Treatment of patients with HER2-positive metastases with a systemic regimen containing tucatinib (Tukysa), trastuzumab (Herceptin), and capecitabine (Xeloda) induced intracranial responses, prolonged overall survival (OS), and improved patient-reported quality of life (QOL), according to the phase 2 TBCRC049 study presented at the 2024 ASCO Annual Meeting (NCT03501979) Preliminary data in breast cancers with leptomeningeal metastases, including target-deficient breast cancers at baseline.

Among evaluable patients with target neurologic deficits at baseline (n = 12), 58% had improvement in deficits and 5 patients had a best response of stable target deficits. Six of seven patients with improvement in target deficits experienced this at first restaging. Of note, no patients received steroid therapy during this period.

In addition, all 13 response-eligible patients achieved clinical benefit with the regimen, with eight patients achieving stable disease and four achieving partial responses (PR), including one patient who achieved a PR at cycle 3 and became a complete response (CR) at cycle 9. The ORR rate for leptomeningeal objective response per composite criterion was 38%.

Overall survival was also improved in this population, with four patients still alive at the time of last follow-up, July 21, 2021. Further evaluation of patient-reported outcomes and quality of life showed that patients' mean MD Anderson Symptom Inventory (MDASI) and Linear Analogue Self-Assessment (LASA) scores improved over time, indicating improved quality of life.

This is the first prospective study to demonstrate that systemic therapy results in intracranial response, improved symptoms, improved quality of life, and prolonged survival in patients with leptomeningeal breast cancer. These data support systemic therapy as initial leptomeningeal treatment for HER2-positive breast cancer.

Tucatinib in combination with trastuzumab and capecitabine was approved by the FDA in April 2020 for the treatment of patients with HER2-positive breast cancer, including those with brain metastases, who have received at least 1 prior HER2-based treatment regimen in the metastatic setting. The investigator-initiated, nonrandomized TBCRC049 study was designed to evaluate the efficacy of this tucatinib-based regimen in patients with leptomeningeal metastases from HER2-positive breast cancer.

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

Of the 17 patients enrolled, 47% had abnormal cerebrospinal fluid cytology and 88% had symptoms of leptomeningeal metastases. MRI showed evidence of leptomeningeal metastases in all patients, and 82% also showed brain metastases; 65% had previously been treated for brain metastases. Patients received a median of 5 (range 2-27) 3-week treatment cycles. Leptomeningeal composite ORR as well as patient-reported outcomes and QOL were assessed, and up to 4 target neurologic deficits were identified per patient.

Response assessment included neuroclinical examination, cerebrospinal fluid pathology, and MRI neuraxial imaging using a standardized scorecard. To qualify for leptomeningeal composite response, patients must demonstrate improvement or stabilization of target deficits based on neurological clinical assessment, negative cerebrospinal fluid cytology following a positive result at baseline, and demonstrate radiographic PR or CR based on central nervous system imaging. Neurologically/clinically defined progression requires worsening of the target deficit, negative or positive cerebrospinal fluid cytology, and stable central nervous system imaging. Radiographic progression was defined as stabilization or worsening of the target defect, negative or positive CNS cytology, and disease progression.

In the overall population, 4 patients were deemed not evaluable for efficacy due to study discontinuation before the first restaging. Reasons for discontinuation included toxicity (n = 1), patient selection (n = 1), or disease progression (n = 2). By the time of last follow-up, 12 patients had discontinued treatment due to progression of leptomeningeal metastases, and 7 of these patients also had central nervous system progression. Three patients discontinued treatment due to systemic progression.

Major study limitations include the lack of central review of imaging findings and the small number of participants. Furthermore, there is no validated comprehensive response assessment for leptomeningeal metastases, although response assessments proposed in the Neuro-Oncology-Leptomeningeal Criteria were employed.