Targeted therapy shows continued promise in patients whose tumours had NTRK gene fusions
Dr David Hong - University of Texas MD Anderson Cancer Center, Houston, USA
LOXO101 is really the first selective inhibitor of TRK and we started the trial almost two years ago. Really it was designed as a traditional phase I trial but we began enrolling patients with known TRK fusions and have seen some remarkable responses in these patients.
Tell me about the results.
NTRK is a really interesting gene. It was initially defined as a gene that is involved in the central nervous system and involved in signalling and function of both the central and peripheral nervous system pathways such as proprioception, pain sensation etc. But in the 1980s they began finding that there were certain cancers that actually had abnormal fusion pairings or fusion proteins of the NTRK gene with other partners. What they discovered was that these fusion partners led to this oncogenic addicted event in these cancer cells. So when we started the study we knew that there was a small prevalence of these fusion patients, or tumour patients, in the population but we weren’t sure how many because the data, the literature data, is not that robust. But as we began enrolling these patients we began seeing these responses in patients. So far to date we have now enrolled a total of seven patients with NTRK fusions of all different histologies and six of those patients that have been restaged so far have had some level of significant response.
How does this differ from entrectinib?
Yes, entrectinib targets both ALK, ROS and TRK, LOXO101, however, is a much more specific drug than entrectinib in the sense that it only really targets TrkA, B and C. The drug itself is designed so that it would really not have any other off-target effects. That’s important in the context of what’s called the therapeutic window – the more specific you are the less off-target side effects that you may have and the more drug that you can deliver and the more specific drug that you can deliver.
What about toxicities?
There have been, we think. The trial itself really looked at all side effects, whether they were related to the actual drug versus related to the underlying cancer. But TRK inhibitors have been known to cause things like dizziness and we did see dizziness, as did entrectinib. But beyond that, the drug has really been fairly well tolerated and we’ve had patients on now for over a year without any major significant side effects.
What about advanced clinical trials?
There’s an ongoing basket study, a LOXO phase II trial, that I’m also a partner, a PI, on with a number of other centres. The idea is really to try to hone down the signal in patients with TRK fusions. We know that they’re out there, we know that they can be rare or they can be very common in certain rare tumour types. So the idea is to figure out if in these patients with multiple different tumour types with TRK fusions how active this drug is.
Which tumour types?
We’ve learned a couple of things about the patients that we think may likely harbour these TRK fusions. One, again it’s present likely in multiple different histologies, not just one specific tumour like lung cancer. Two, it seems to tend towards younger patients. A lot of our patients that we enrolled on this study that were found to have TRK fusions were under 50. Three, we think that the prevalence of this tumour is more common in certain subsets of histologies, for example MASC tumours, mammary analogue secretory carcinomas which oftentimes have been misclassified as either acinic cell tumours or parotid cancers. They likely have an almost 80% chance that they will have these NTRK fusions. Too we’ve seen papillary thyroid cancer patients in younger patients and there’s literature out there now suggesting that in over a quarter of these patients, young patients with aggressive papillary thyroid cancer patients, they may actually harbour the NTRK fusions. We’ve seen now in certain types of sarcomas like GIST tumours that are negative for cKIT and PDGFRA may also harbour these NTRK fusions. We really think that these fusions are likely oncogenic drivers, that means they are present in patients with lung cancer and other sarcomas that do not have other mutations that are driving the tumour such as BRAF, EGFR or ALK/ROS.
What is your take home message?
My hope is that we will have a fair number of patients in the basket study to really update everyone at AACR next year. It’s early to say if these high response rates will pan out over a large number of patients but it’s really encouraging, at least, right now. So far both the entrectinib and this LOXO101, almost everybody who has had an NTRK fusion have responded. So that’s very encouraging. My hope is that by next year, whether it’s me or somebody else, to present some preliminary data on the basket study and how that’s going. But we’re also excited to note that the next generation of TRK inhibitors have already been developed, LOXO195. We know that there are mutations that can arise that specifically confer resistance to the existing TRK inhibitors including LOXO101 but Loxo and [?? 6:48] have already developed drugs that we think can overcome that mechanism of resistance and we’re already planning another study for those resistant patients in 2017.