TRK Inhibitors: Evolution of a Tumor-Agnostic Treatment Approach - Episode 10
David S. Hong, MD: How will the availability of TRK inhibitors change clinical practice? I think larotrectinib—and also other TRK inhibitors—is really one of many firsts because it’s the first histology agnostic treatment approved, small molecule inhibitor approved, based on genetic abnormalities, right? And I do think that there will be other similar agents that arise in the next several years. And so how that will change practice is that increasingly, the importance of multipanel next-generation sequencing [NGS] testing will be crucial to help identify these patients who have really truly profound transformative benefits from some of these drugs.
I think one message I want to get out of this is for those who are out there, if you have the opportunity to test your patients, if patients are listening to this is, they try to get themselves tested or that the oncologists go out and test them for an NGS panel. I’m not a spokesman for any of these testing agencies. I just realize how powerful it can be if we can identify these patients who have truly driving oncogenic alterations that we have drugs for.
David Hyman, MD: The biggest impediment to the use of TRK inhibitors in the clinic is really testing and identifying patients who harbor TRK fusions. I think that ultimately this is going to happen predominantly through the use of larger panel type testing where you have the ability not only to test for TRK fusions, which again can be something like a half a percent event depending on the cancer type, but also all the other actionable alterations and the other tumor agnostic biomarker, microsatellite instability. So through a single genomic test, you screen for both tumor specific and tumor agnostic biomarkers in that patient. And among those who obviously harbor TRK fusions, I would certainly recommend that they be treated with TRK inhibitors.
I’m often asked about the sequencing of TRK inhibitors relative to other therapies, and the FDA label does say that patients should have had an existing standard of care or can receive it first-line if no standard of care exists. But I really would encourage people to consider using these agents relatively early due to their incredible efficacy profile, response rates of approximately 80%, the durability of response, and importantly the quality of life associated being on these agents.
I think that given the really profound activity and excellent safety profile of these agents, these really should be considered relatively early in the course of treatment. However, if you do encounter a patient who’s incredibly ill and might be too ill, for example, to receive even standard chemotherapy, and they do have a TRK fusion, I would encourage trying that agent even in a patient who you otherwise might not feel is fit for standard chemotherapy. Because again, we have seen the ability for these agents to bring people back from the brink of death even when they’re very sick from this disease. So if we find a TRK fusion, I would ultimately hope that the patients would receive these agents.
David Reardon, MD: I feel it’s important to utilize these agents in the treatment of our patients whose tumors have the TRK mutations and fusion transcripts. One of the important research questions we need to be evaluating as more studies are conducted is the timing of when to administer these drugs for patients. Should they be used in patients when they’re newly diagnosed? Should they be reserved for patients who had progressed after standard of care therapies or established therapies? And another important research question is whether they should be incorporated or combined with other agents to further enhance their clinical benefit as well as the durability of benefit that these agents have the potential to achieve.
I think, in general, it makes sense to try to think about evaluating the potential of these agents earlier on in the course of the disease because we know as tumors recur, they tend to pick up additional mutations, additional drivers. And the therapeutic benefit that we may have by a targeted therapy blocking the specific cancer driver may lose its benefit in the recurrent setting if additional driver mutations are acquired as the tumor is exposed to other therapies and develops resistance. So my personal bias would be that they would have their biggest impact most likely earlier in the course of the disease, but I think that’s a very important point we need to be evaluating with ongoing clinical research studies and trials.
There are a number of targeted therapies that are able to target multiple potential drivers in the tumor that are relevant to the tumor biology. And then there are other targeted therapies that are much more specific and focused on single drivers. In general, the preference for many oncologists is to utilize the inhibitors that are more specific because they tend to have fewer adverse effects for patients. The inhibitors that are broader and hit a number of different targets may have more adverse effects due to secondary effects of the drugs on other pathways and other tissues and organs in the body.
In general, for therapies that are quite specific and focused, such as larotrectinib and the other TRK inhibitors that are moving forward now for oncology patients, that’s one of the keys to their safety and their excellent tolerability. They are quite specific. They really are capable of affecting the tumor and having minimal impact on normal tissues and organs of the body.
Transcript Edited for Clarity