TRK Inhibitors: Evolution of a Tumor-Agnostic Treatment Approach - Episode 7
David Hyman, MD: In pediatric cancers, NTRK fusions occur as common events in certain rare cancers. One of these cancers is a sarcoma called infantile fibrosarcoma, and this often presents as sarcomas on the extremities of a child and previously would often require radical surgeries and sometimes even amputation to try to achieve a cure, which sometimes wasn’t possible. Really, in the best-case scenarios, children were often being scarred for life by these surgeries or somewhat disabled. One of the amazing uses of larotrectinib has shown the ability to use it in a preoperative fashion to downstage these cancers and allow much more minimal and potentially curative surgeries, where some of these children have been able to come off of larotrectinib postoperatively and remain cancer free. That’s really a remarkable story.
We also see TRK fusions in some other rare pediatric cancers like congenital nephromas and a number of other pathognomonic cancers in which these occur. There’s also a condition called secretory breast cancer, which is a juvenile rare form of breast cancer. And again, TRK fusions occur in that about 90% of the time. So these are in distinction with some of the adult cancers where these are rare events in common cancers. We have TRK fusions in many of the pediatric cancers being common events in rare cancers. There are also some pediatric gliomas or brain tumors where we see TRK fusions also occur, and we have data that were presented at ASCO [American Society of Clinical Oncology] this year, 2019, that show that larotrectinib can be active in that patient population as well, with some durable benefit and responses.
David Reardon, MD: The important information we need to know when using these TRK inhibitors in pediatric patients is that the tumor has been appropriately screened for detection of the appropriate mutation that these drugs are inhibiting or blocking. Those types of genomic analyses—or it can be done with FISH [fluorescence in situ hybridization] or RT-PCR [reverse transcription polymerase chain reaction] analyses—are now regularly or routinely done at many academic centers in particular, and patients and families have access to these testing materials for analysis, direct analysis, of the tumor material. So those pediatric patients in whom these analyses have identified mutations involving the TRK gene, or fusion transcripts, ought to be the patients who are prioritized for a treatment with these exciting new agents.
David Hyman, MD: The treatment of pediatric cancers has really been a central pillar of the larotrectinib experience. And when we look at the pediatric patient population, this is a population where we see response rates sometimes in excess of 90%. These are incredibly high response rates. And many of these children, because of the scenarios in which these drugs are being given, may even have the opportunity to receive potentially curative therapy. They’re bridged to that through the use of larotrectinib and come off of this drug. So that’s really potentially a life-changing event for those kids. The other feature is that children seem to tolerate these drugs incredibly well, with really none of the neurocognitive effects that we sometimes see in adults.
Again, because the landscape of TRK fusions is somewhat different in pediatric cancers where we know certain histologic subtypes are going to harbor TRK fusions as a common event, I actually expect that a lot of the initial use of TRK inhibitors will be in these pediatric patients where the community has a high degree of understanding of where these occur and can really focus their testing. And I think we’re going to see massive and rapid adoption of testing that has the ability to detect these TRK fusions in the relevant pediatric cancer types. And that community is really going to organize around incorporating TRK inhibitors very early in the paradigm of managing these children.
Transcript Edited for Clarity