Targeted Cancer Therapies Showing Promise in Treating Parenchymal Brain Metastases

In a recent paper, researchers compiled the most recent evidence on predictive biomarkers for treating parenchymal brain metastases (BM), a common cause of mortality and morbidity in patients, as more data comes to light on which molecular alterations show clinically meaningful efficacy when targeted.

The learnings on treating parenchymal brain metastases stem from several solid tumors, most commonly non-small cell lung cancer (NSCLC), breast cancer, and melanoma, all of which have benefitted from targeted treatments in recent years.

“Intracranial efficacies were postulated for several next- generation tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors during the last decades in patients with BM from different solid tumors. However, targeted- and immuno- therapy were fully efficient only in a selected number of patients underscoring the need for biomarkers to support appropriate selection of individualized treatments and maximize clinical benefits for BM patients,” explained the researchers. “In addition, although finding of recent studies appeal for performing molecular testing of BM, tissue availability still present a clinical obstacle.”

Currently recommended for all patients with NSCLC, biomarker testing has revealed various targetable molecular alterations in the disease. Notably, patients who have targetable mutations are associated with a higher risk of BM. These targetable mutations with implications for BM include:

• Epidermal growth factor receptor (EGFR): Targeted therapies like afatinib and osimertinib have showed intracranial responses of 66%-81.8% and extracranial responses of 77%-82.1%.
• ALK arrangements and ROS1 gene rearrangements: Targeted therapies alectinib, lorlatinib, and brigatinib have elicited intracranial response rates of 63%-85.7%.
• BRAF mutations: Extracranial response rates of 63.3% have been reported with dabrafenib/trametinib.
• PD-1/PD-L1 expression: With immunotherapies like nivolumab, pembrolizumab, and atezolizumab, intracranial response rates of 9%-33% and extracranial responses of 11%-33% have been reported.

Several molecular alterations have also played a large role in breast cancer due to its heterogeneity, although the role that targeted therapies for these alterations has on BM is less clear. For example, hormone receptor expression, present in two-thirds of patients with breast cancer, has a lower association with BM. For patients who do experience BM, loss of estrogen or progesterone receptor expression is common, occurring in half of patients. For patients with HER2 overexpression, various targeted therapies have showed responses in BM, with intracranial rates ranging from 40.6% with tucatinib to 70% with trastuzumab emtansine.

In melanoma, BM is reported in one-third of patients at diagnosis, and half of patients eventually develop BM.

“Considering the high propensity of metastatic spread to the brain in melanoma, therapeutic approaches with intracranial efficacies have revolutionized treatment and survival in brain metastatic melanoma during the last decade,” wrote the researchers. “However, identifying patients benefiting the most from treatment strategies presents a frequent obstacle in clinical therapeutic decision making.”

With half of patients with melanoma harboring a BRAF mutation, patients often receive dabrafenib/trametinib or vemurafenib/cobimetinib, which have demonstrated intracranial response rates of 18%-58% and extracranial response rates of 33%-75%.

Reference

Steindl A, Brastianos PK, Preusser M, Berghoff AS. Precision medicine biomarkers in brain metastases: applications, discordances, and obstacles. Neurooncol Adv. 2021;3(suppl 5):v35-v42. doi:10.1093/noajnl/vdab105