TRK Inhibitors: A Tumor Agnostic Targeted Therapy - Episode 4

Entrectinib's Value as a TRK Inhibitor


Alexander Drilon, MD: Entrectinib is a multikinase inhibitor with activity against TRK A, B, and C, but also against the other kinases, ALK and ROS1. It’s been tested in various settings, and the publicly available data show activity of the drug against 4 cancers that harbor an NTRK rearrangement or fusion. All 4 of these cancers have either confirmed responses to therapy or volumetric shrinkage. Based on this data in part, the drug has received an FDA breakthrough therapy designation for the treatment of solid tumors that harbor an NTRK fusion.

The combined analysis of the entrectinib phase I data was based on 2 separate trials. One was the ALKA trial that was predominantly run out of Europe, and the second trial was called STARTRK-1, a very interesting name. That was a global multicenter effort. This development program established the recommended phase II dose of 600 mg daily of the drug looking across both cohorts of patients.

In the aggregate dataset of the ALKA and STARTRK-1 trials, there were 4 patients whose cancers harbored an NTRK fusion. This was a mix of histologies including colorectal cancer, non—small cell lung cancer, mammary analog secretory carcinoma, and astrocytoma. The data echo the activity that we’ve seen with larotrectinib, meaning that there was also a tumor agnostic response to therapy. All 4 of those cases either had confirmed radiologic responses to therapy or, in the case of the primary brain tumor, a volumetric reduction in therapy. And so, we’re seeing similar parallels to what we’ve noted in the larger larotrectinib dataset. This also occurred across different ages and across different upstream fusion partners.

We have less clinical data for entrectinib compared to larotrectinib, but looking at the limited dataset of 4 patients with NTRK rearranged cancers, you’ll see that these fusions had a variety of different 5’ upstream gene partners. Similar to the larotrectinib data, it didn’t seem to matter what the upstream gene partner was. You had a possibly equal likelihood of response to therapy with this drug.

The phase II trial of entrectinib takes from the original phase I name for the global multicenter trial called STARTRK-1, and the phase II trial is called STARTRK-2. That’s currently exploring the activity of entrectinib in NTRK-fusion positive cancers, and it’s a basket trial. There’s also an ongoing pediatric protocol called STARTRK-NG.

Transcript Edited for Clarity