Intracranial Efficacy of Entrectinib Among Patients With NTRK Fusion-Positive CNS Metastases

PracticeUpdate: One of the interesting presentations this year looks at the CNS activity of entrectinib for patients with CNS metastasis. How is this drug designed to work?

Dr. Stupp: NTRK fusion has been recognized as an oncogenic driver in certain solid tumors and this drug, entrectinib, has been developed specifically to target NTRK fusion, also ROS and ALK tyrosine kinases. And this compound has been optimized to cross the blood-brain barrier. At this ESMO, an update has been provided on a subgroup of patients, 74 patients, being treated in a total of three clinical trials, who had metastasis to the brain. Response rates between 50 and 60% with entrectinib have been demonstrated in a subgroup analysis in the brain.

I think what it really shows is that response to entrectinib in the central nervous system is similar to the response we see in visceral disease. So the dogma that for the brain you need to radiate, you need stereotactic radiation, should really be revisited. We have now compounds that are active, that penetrate sufficiently to the brain, and give similar response rates. We see that with many of the tyrosine kinases and entrectinib is another example.

What is important with entrectinib is that this drug has now been approved. We have now two NTRK inhibitors approved, entrectinib and larotrectinib, and both are histology-agnostic. So what you need to prove is the presence of this fusion rather than a certain disease that presents with clinical parameters.

PracticeUpdate: What did earlier results from the clinical trials of entrectinib show about its systemic activity?

Dr. Stupp: Entrectinib has been shown also in systemic disease, whether this is lung cancer, whether this is sarcoma, some salivary gland cancer, colorectal cancer (when it was actually, the first time seen in the 1980s, this fusion and this inversion of chromosome 1), in some thyroid cancer, that you have a high response rate with treatment with entrectinib. So targeted treatment for a targeted driver mutation. That's, at least for some patients, the dream of personalized medicine and targeted medicine that comes true.

PracticeUpdate: Based on the results from this study, how active is that drug in CNS?

Dr. Stupp: Entrectinib in the CNS has similar activities: response rate 50-60%, response duration 8-9 months. It may be longer. These patients, overall, have different prognoses from their tumor, so there's still much to be learned, but it's clearly the first choice when you have a patient with CNS disease and NTRK fusion presence.

PracticeUpdate: Does it appear that entrectinib demonstrates activity irrespective of primary tumor type?

Dr. Stupp: Yes. NTRK activity is independent of the tumor type. It's present in many tumor types, probably in almost any tumor type, but the frequency is on average 1% or less, so it's hard to detect. You only find it when you now do molecular screening, NGS, looking for those fusions in a systematic way. But for those tumors that harbor this driver mutation, entrectinib or larotrectinib is the treatment of choice. Of importance, both drugs, larotrectinib and entrectinib, have been approved both by the FDA and earlier this year by EMEA and are histology-agnostic. So, it is really based on the molecular makeup of the tumor.