Palbociclib Demonstrates Activity Against Progressive Brain Metastases Harboring CDK Pathway Alterations
Key findings
- This proof-of-concept study evaluated the efficacy of palbociclib, a cyclin-dependent kinase (CDK) inhibitor, against brain metastases in patients who had CDK pathway alterations detected on intracranial or extracranial tumor tissue
- In this interim analysis of 15 patients (13 with alterations detected on intracranial tissue), the study met its primary endpoint, demonstrating stable disease in 53% of patients at eight weeks
- Intracranial efficacy was observed for all tumor types studied (3 of 5 patients with breast cancer, 1/5 with melanoma, 2/3 with esophageal cancer and 2/2 with lung cancer)
- The median time to intracranial disease progression for the eight patients who experienced intracranial benefit was 6.4 months, and median overall survival was also 6.4 months
- Physicians should consider ordering molecular analysis of archival brain metastatic tissue, if available, to inform the choice among CNS-penetrant targeted therapies
Traditionally, targeted systemic therapy for brain metastases is selected based on analysis of the primary tumor. As a logical next step toward better treatment, researchers at the Massachusetts General Hospital Cancer Center have been researching genomic differences between primary tumors and extracranial and intracranial metastases.
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Two of those studies, one published in Cancer Discovery and the other in Nature Genetics, implicated the cyclin-dependent kinase (CDK) pathway as a driver of multiple types of solid tumors into the central nervous system (CNS). That and other work suggests CDK alterations are a promising target for treating brain metastases.
In Nature Cancer the researchers recently presented promising interim results from a proof-of-concept study. They showed the CDK inhibitor palbociclib was effective against brain metastases from four tumor types when patients were selected based on genetic testing. The authors are Priscilla K. Brastianos, MD, Albert E. Kim, MD, Daniel P. Cahill, MD, PhD, Ryan J. Sullivan, MD, and colleagues.
Methods
15 adults with progressive CNS metastases and a CDK pathway alteration on tumor tissue were enrolled between February 2017 and September 2019. The alterations were detected via molecular analysis of intracranial tissue in 13 patients; the others had extracranial tissue analyzed. The tumor types studied were breast (n=5), melanoma (n=5), esophageal (n=3), and lung (n=2).
Oral palbociclib was administered at 125 mg/day for 21 days followed by seven days off to complete a 28-day cycle.
Efficacy
The protocol specified the primary endpoint would be met if six or more patients had intracranial benefit (complete response, partial response or stable disease) eight weeks after palbociclib initiation. Eight patients (53%) had stable disease at that timepoint. Intracranial benefit was observed for all tumor types.
Other efficacy endpoints were:
- Median overall survival—6.4 months
- Median time to intracranial disease progression (TTP)—9.0 weeks
- Median TTP for the eight patients with intracranial benefit—6.4 months
Three patients survived ≥2 years (two with breast cancer and one with melanoma).
Toward a Change in Paradigm
These data provide further support for a new approach to treating brain metastases. Molecular analysis of intracranial tumor tissue, when available, can inform the choice between CNS-penetrant therapies (e.g., those targeting PI3K or NTRK/ROS1 mutations).
The Mass General team is helping to recruit for a multicenter, prospective, genomically guided phase 2 trial that will evaluate three such therapies: abemaciclib, paxalisib and entrectinib.
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