Triplet Regimen Extends Time Before Brain, Spinal Cord Metastases Worsen in Patients With Breast Cancer

Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer who were assigned to receive a three-drug regimen of Tukysa (tucatinib), Ibrance (palbociclib) and letrozole saw an increase in the amount of time it took for their disease to progress to the central nervous system, known as central nervous system (CNS) progression-free survival (PFS), according to recent research.

Previous results from the trial showed that the combination had an acceptable safety profile and encouraging antitumor activity in this population, while this poster presentation presented during the 2021 San Antonio Breast Cancer Symposium focused on data from an exploratory analysis of intracranial efficacy in patients who had CNS metastases.

Findings from the phase 1b/2 clinical trial showed that in 15 patients with CNS metastases (where disease had spread to the brain and/or spinal cord), the average CNS-PFS was eight months with the triplet regimen. Additionally, at the one-year mark, 20% of patients did not experience disease progression to the CNS, and at the two-year mark 13% of patients did not have CNS progression.

“The majority of patients had treated (non-measurable) CNS lesions, limiting the evaluation of CNS response and biasing outcome towards stable disease [SD],” lead study author Dr. Elena Shagisultanova, of the University of Colorado Cancer Center, and colleagues, wrote in a poster on the data. “Moreover, we demonstrate the ability to get prolonged clinical benefit with this regimen post first CNS progression in carefully adjudicated cases.”

For the trial, researchers examined the combination of a HER2-targeted tyrosine kinase inhibitor (TKI), a CDK4/6 inhibitor, and an anti-hormonal agent in patients with hormone receptor-positive, HER2-negative metastatic breast cancer who had untreated asymptomatic or treated stable CNS metastases.

To be eligible for enrollment, patients needed to be post-menopausal or premenopausal on ovarian suppression. Moreover, they must have received two or more HER2 inhibitors at any time of their disease, one or more HER2-targeted agents in the metastatic setting and up to two endocrine agents for metastatic disease. Patients were allowed to have received prior treatment with letrozole. However, if patients received prior treatment with HER2-targeted TKIs or CDK4/6 inhibitors, they were excluded.

Study participants received Tukysa twice a day; daily Ibrance for 21 days on and seven days off; and daily letrozole. Researchers examined the drugs’ activity and CNS-PFS, which was defined as intracranial (within the skull) progression or death, and bi-compartmental PFS.

Within the 15 patients with CNS metastases, the average age was 47 years (range, 22 to 70), and the average number of prior lines of therapy received for metastatic disease was two (range, 1 to 5). Additionally, nine patients (60%) received prior CNS radiation, one patient (7%) underwent neurosurgery alone, three patients (20%) underwent neurosurgery and radiation, and two patients (13%) did not receive any prior treatment for CNS disease. All patients had previously received HER2-targeted therapy with Herceptin (trastuzumab) and Perjeta (pertuzumab) and five patients received Kadcyla (ado-trastuzumab emtansine; T-DM1).

Of the 15 patients enrolled to the trial, 14 were evaluable for disease; one patient was determined to have non-evaluable disease because they had no evidence of disease in the CNS for 24 months. At a data cutoff date of Nov. 1, 2021, 12 patients had received treatment; five of these patients had stable disease (SD) for six months or longer with the combination, six had SD for fewer than six months and one experienced a complete response.

Two patients were not treated; one patient who had a non-measurable dural lesion (meaning that it was found on the dura, the outer layer covering the brain and spinal cord) had SD for five months, and the other patient had a measurable lesion and had SD for eight months.

Regarding safety, prior data showed that the most common severe side effects reported with the triplet regimen included neutropenia (a decrease in white blood cells called neutrophils; 58%), leukopenia (white blood cell reduction; 24%), diarrhea (17%) and fatigue (14%). Notably, these side effects were determined to be manageable. Moreover, no cases of brain swelling were reported in patients with CNS metastases, including those who received radiation for isolated CNS progression during the study.

A version of this article was originally published on OncLive as, “Tucatinib Plus Palbociclib/Letrozole Prolongs CNS-PFS in HR+/HER2+ Breast Cancer.”

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