Intracranial Efficacy of Tucatinib, Palbociclib, and Letrozole in Patients with Hormone Receptor–Positive, HER2-Positive Breast Cancer with Brain Metastases

This phase 1b/2 clinical trial looked at the combination of tucatinib, palbociclib, and letrozole in extensively pretreated patients with hormone receptor–positive, HER2-positive metastatic breast cancer, specifically central nervous system (CNS) metastases.1 We will look at the data on the intracranial effectiveness of this combination treatment in these patients with brain metastases.1

The trial only included patients with hormone receptor–positive, HER2-positive metastatic breast cancer who had previously been treated with ≥2 HER2-targeted therapies.1 Patients with untreated asymptomatic CNS metastases or treated stable CNS metastases were permitted in the study. The best confirmed CNS responses were summarized.1 CNS progression-free survival (PFS), defined as intracranial progression or death, and bicompartmental PFS (CNS and/or non-CNS progression or death) were evaluated, and the best CNS responses were summarized.1

There were 15 CNS metastasized patients in the study. Two patients had untreated asymptomatic CNS metastases, 12 patients had treated stable CNS metastases, and 1 patient had resection of a solitary CNS metastases prior to starting study treatment.1 This patient had no evidence of CNS disease for 24 months on the study.1 The majority (13 of 14) of patients with evaluable disease had stable disease.1 Six of these patients had stable disease for ≥6 months, 7 had stable disease for <6 months, and 1 patient who had stereotactic radiotherapy to a 1.8-cm cerebellar lesion prior to enrollment had a complete CNS response after 4 months on the study.1 Of the 2 patients with untreated CNS lesions, 1 patient with no measurable disease had stable disease for 5 months on the study, and 1 patient with measurable disease had stable disease for 8 months on the study.1 With a data cutoff of June 31, 2021, and a median follow-up of 15 months, the median CNS-PFS was 8 months, with 20% of patients reaching a CNS-PFS of ≥1 years.1 The PFS for bicompartmental patients was 9 months. Ten patients left the study due to progressed disease.1 Half of these patients had CNS-progressed disease.1 Three patients had systemic and CNS progression, while 2 patients had systemic disease progression only.1 Three patients are still enrolled in the study, with follow-up periods at 15, 16, and 28 months planned.1

Because the majority of patients had treated CNS lesions, CNS response evaluation was limited and skewed toward stable disease.1 The prolonged CNS-PFS in this small patient subset, however, implies that this nonchemotherapy-based targeted regimen has some antitumor efficacy in the CNS.1


  1. Nader-Marta G, Martins-Branco D, Agostinetto E, et al. Intracranial efficacy of tucatinib, palbociclib and letrozole combination in patients with HR+/HER2+ breast cancer and brain metastases. 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. P1-18-26.

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