TRK Inhibitors: Evolution of a Tumor-Agnostic Treatment Approach - Episode 8

TRK Inhibition in CNS Tumors or Metastases


David Reardon, MD: There are many challenges associated with the management of patients with primary and secondary or metastatic CNS [central nervous system] tumors. These can be quite complex tumors with multiple factors often contributing to driving tumor growth and proliferation, invasion and destruction of the normal CNS tissues. Therefore, our patients suffer from significant neurologic deficits and difficulties, and it’s paramount to be able to identify drugs that can effectively penetrate through the blood-brain barrier and get into the tumor and have an important impact on controlling the growth and ideally killing off the tumor cells.

TRK mutations and fusion transcripts have been identified as significant drivers, major drivers, of various tumors involving the CNS, both primary and metastatic tumors. They are present within a small percentage of primary glial neoplasms in both the pediatric and adult populations of patients. But due to the lack of effective therapies for these patients, it’s imperative—if we have a treatment that could make a difference and have an impact like these TRK inhibitors are showing—that we identify these patients and appropriately analyze the tumor samples to identify which patients would be appropriately treated.

Outcome for both pediatric and adult patients with primary glial tumors is quite poor with our traditional standard of care therapies of surgery, radiation, and chemotherapy. These are intrinsically infiltrated and destructive tumors. Patients typically rapidly develop significant serious neurologic deficits and adverse effects. Any treatment that can have an impact on controlling that process and potentially killing off the tumor cells would be meaningful and have a significant impact, particularly if it lacked significant systemic or neurologic adverse effects. Unfortunately, radiation and chemotherapy are the treatments that we have as our standard therapies and come with a significant frequency of adverse effects for patients.

There are some very exciting preliminary data that are emerging about the activity of these TRK inhibitors for patients with primary and metastatic brain cancers. There was an exciting abstract presented at the 2019 American Society of Clinical Oncology meeting in which I believe 14 patients with primary or metastatic CNS tumors were treated with larotrectinib. These patients had all had standard therapies with radiation and chemotherapy. Five of the patients had metastatic CNS tumors and 9 of the patients had primary CNS glial neoplasms.

Among the metastatic CNS tumor patients, 3 out of the 5 patients achieved a radiographic response. One patient achieved a stable disease, and these responses were durable for up to over a year. For the patients with the primary glial neoplasms, again, they had progressed on prior therapy so there was no identified available agent that had a significant likelihood of benefiting these patients. Of those 9 patients, 1 achieved a radiographic response, and 7 achieved stable disease. And again, the durability of benefit was out to 9 months, and ongoing at the time of the report, which was very exciting and encouraging for these challenging tumors.

The other important aspect that was described in the study was the safety of these agents. That’s something that’s been documented now in many different studies for different patient populations but appears to be equally true for patients with primary and secondary CNS malignancies, such that in general, these agents are quite safe and well tolerated with adverse effects that are generally limited to grade 1 or grade 2 events.

Transcript Edited for Clarity