Jochen H. Lorch, MD, MS: There were a number of trials conducted using larotrectinib and similar trials using entrectinib. Those started out as phase 1 trials, which were tissue agnostic. Any tumor with an NTRK fusion was included, and in some cases there were also NTRK mutations allowed. In the LOXO-101 study that was for larotrectinib, children were also included. This was followed by cohort expansions on this trial. It turns out that the efficacy in general was very good, with radiographic response rates above 70%. That was also true for thyroid cancer. There were cases that did not reach the amount of shrinkage necessary for a partial response. In most cases, there was some shrinkage that was still appreciated, and more than half of all patients were still alive and on treatment at the 1-year mark.
Have these data been practice changing? Well, my feeling is that yes, based on the impressive efficacy and also the general absence of severe adverse effects, especially compared to the standard of care in iodine-refractory thyroid cancer, which is lenvatinib and sorafenib, where numerous cases require dose reductions and dose modifications. All this is much less of a problem with larotrectinib and also entrectinib. So these are good treatment options for patients with an NTRK fusion.
In terms of monitoring, I typically get CT scans every 2 months to assess for a response, and otherwise I follow patients pretty closely clinically with routine laboratory tests and physical examinations perhaps 1 week or 10 days after initially starting the treatment, but then spread out the intervals increasingly. I usually end up seeing patients perhaps once per month while on treatment.
What do we know about resistance mechanisms for NTRK-targeted therapy? For larotrectinib, just like with entrectinib and any other tyrosine kinase inhibitor for that matter, eventually resistance occurs, and there are recurring new mutations that are found in these tumors that typically affect the ATP [adenosine triphosphate] binding site, making it impossible for the drug to bind to its target. There are second-generation NTRK inhibitors in development and in early clinical testing that are trying to overcome this resistance.
What is my personal experience with larotrectinib, and entrectinib for that matter, because I consider them very similar? Well, these are very well-tolerated drugs and there’s really no comparison to the old multityrosine kinase inhibitors, such as lenvatinib or sorafenib, and the efficacy has been great. So far I’ve seen responses in all cases. It’s perhaps important to note that not all cases respond, but if you look at these cases more carefully, it often turns out that if there was an NTRK fusion detected, it was not one of the clinically meaningfully ones. Also for NTRK mutations, not the fusions, but the mutations, it seems that the responses are much lower. I suspect that many of these mutations that are found in next-generation sequencing of NTRK are just bystander mutations that have no clinical implications. It’s therefore not surprising that targeting NTRK in that scenario does not work.
A good confirmatory test I think is still immunohistochemistry to look for overexpression of the protein. There’s also a confirmatory testing that’s possible based on RNA sequencing. This is a more specialized test, but it’s frequently and increasingly widely available. Especially for cases where there are questions about whether this is meaningful, then this additional testing may be helpful. In cases where there is no urgent need to have a response because there’s not bulky disease or there’s no disease that’s immediately life threatening, then one could also just try to treat and assess for a response. If there is no response, then it was probably not a meaningful mutation or fusion, and if there is, then use that as a confirmation that the sequencing provided some reasonable data.
What’s often seen in cases that are truly NTRK fusion positive and where this is the significant driver of the disease, is that the duration of response can be quite long. From the early trials, there are still numerous patients who are being treated beyond the 2-year mark with responses still ongoing, which speaks to the efficacy of larotrectinib, also entrectinib I think, but also to the significance of NTRK fusions as a driver mutation of this disease.
As a medical oncologist who sees a lot of iodine-refractory thyroid cancer, it’s been very gratifying to see the emergence of these targeted therapies that really have made thyroid cancer a treatable disease, which it was not back in 2005, before the advent of sorafenib, for example. Now we have sorafenib and lenvatinib for the vast majority of cases, but then we also increasingly have these targeted therapies such as larotrectinib and also entrectinib for, say, NTRK fusion positive cases. We have the BRAF inhibitors for those cases that are BRAF V600E mutated, which also has good efficiency and also with a slightly more favorable adverse effect profile compared to multityrosine kinase inhibitors. Also, with the recent approval of selpercatinib and the anticipated approval of pralsetinib, we have 2 RET inhibitors that are highly effective in RET fusion-positive, iodine-refractory thyroid cancer.
Now we’re seeing this broad spectrum of targeted therapies, and my hope is that this will continue and that we’ll be able to personalize targeted therapies more and more based on the genetic profile in thyroid cancer, just as in most other cancers as well.
Transcript edited for clarity.
Case: A 71-Year-Old Woman With Thyroid NTRK Gene Fusion Cancer
Clinical Workup and Initial Treatment
Follow-Up and Additional Treatment