Palbociclib Shows Activity, Tolerability in Patients With Brain Metastases Harboring CDK Pathway Alterations

November 25, 2019

The CDK4/6 inhibitor palbociclib (Ibrance) demonstrated it was active and well-tolerated in a phase II interim analysis of patients with brain metastases harboring alterations in the CDK pathway, according to a presentation at the 24th Annual Meeting and Education Day of the Society of NeuroOncology.

Priscilla Brastianos, MD

The CDK4/6 inhibitor palbociclib (Ibrance) demonstrated it was active and well-tolerated in a phase II interim analysis (NCT02896335) of patients with brain metastases harboring alterations in the CDK pathway, according to a presentation at the 24th Annual Meeting and Education Day of the Society of NeuroOncology.1

Eight of 14 evaluable patients (57%) had clinical benefit intracranially and 6 patients (43%) had clinical benefit extracranially. The median overall survival of these patients was 6.5 months (90% CI, 3.8-13.6).

“An 80-year-old patient with metastatic esophageal carcinoma, [who] had failed multiple rounds of systemic therapy, radiation therapy, and immunotherapy…had a dramatic response to palbociclib just after 2 months of therapy,” Priscilla Brastianos, MD, said in her presentation.

Brastianos is the director of the Central Nervous System Metastasis Program and an assistant professor of medicine at Massachusetts General Hospital, Harvard Medical School. In her presentation, she said that 50% of brain metastases have alterations in the CDK pathway.

“Up to 25% of [patients with cancer] will develop brain metastases and patients will often develop progressive brain metastases in the setting of stable extracranial disease,” said Brastianos. “Our data from a few years ago showed that primary tumors and brain metastases are often genetically distinct, and this implies that targeted therapies that are appropriate for the primary tumor may not necessarily be appropriate for the brain metastasis.”

The objective of the trial was to identify and investigate the activity of palbociclib in brain metastases.

The trial design was biomarker-driven and enrolled patients with recurrent or progressive brain metastases who had measurable central nervous system (CNS) disease and histologically confirmed solid malignancy. The patients also had tissue available for sequencing taken as a part of clinical care, not a new biopsy. Investigators tested for specific alterations in the CDK pathway, including amplifications inCDK4,CDK6,CCND1,CCND2, andCCNE1, as well as loss ofCDKN2A. They treated the 15 eligible patients with 125 mg of palbociclib orally once a day.

At baseline, the patients received a brain MRI and CT to the chest, abdomen, and pelvis before being started on the CDK inhibitor. Their responses to palbociclib were assessed every 2 months with another MRI and CT to the same areas.

Clinical benefit was the primary end point, defined by complete response, partial response, or stable disease using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group criteria. Using the Simon two-stage design, the trial compared null hypothesis of 10% versus alternative hypothesis of 30%. The trial had to enroll 15 patients, and if it had at least 2 responses, there would be an additional 15 patients enrolled. From there, if 6 of the 30 patients had a response, the treatment would warrant further study.

With the 15 eligible patients treated with palbociclib, the study met the criteria to proceed to the second stage of the trial.

In the trial, there were 7 female and 8 male patients. The mean age was 56 and all patients had an ECOG performance status of 0 or 1. The histology of the patients were a mix between breast cancer, esophageal, melanoma, and non—small cell lung cancer.

“This was a heavily pretreated patient population, with all patients having received some form of surgery, systemic therapies—usually in multiple rounds—and 93% having some form of intracranial radiation,” Brastianos said.

She added that most of the patients (80%) had a loss of CDKN2A for their CDK pathway alteration. Two hadCCND1amplification and 1 hadCCNE1amplification.

The most common treatment-related adverse events (TRAEs) were anorexia, fatigue, and vomiting in all grades. There was only 1 patient with a grade 4 TRAE, which was febrile neutropenia, and the most common grade 3 TRAE was a decrease in WBC count in 2 patients.

When asked if palbociclib showed activity because it has good blood-brain barrier penetration, Brastianos said “what our genomic data [showed is that], at least in part, it is because of genetic heterogeneity…there's also break down of the blood-brain barrier with brain metastases. So palbociclib is getting into the brain more than we expected since traditionally it wasn't thought to have too much CNS penetration, yet we’re seeing patients do well on it.”

Because of this interim analysis, a national biomarker-driven trial in brain metastases, Alliance A071701 (NCT03994796), has been initiated. The primary end point will be the CNS response rate and the secondary end points will be overall survival, CNS and systemic progression-free survival, systemic response, and safety.

Reference:

A phase II study of palbociclib in progressive brain metastases harboring alterations in the CDK pathway. Presented at: 24th Annual Meeting and Education Day; November 20-24, 2019; Phoenix, Arizona.