Selecting Treatment for NTRK-Positive Iodine-Refractory Thyroid Cancer

Lori J. Wirth, MD, associate professor of medicine at Harvard Medical School and medical director for the Center for Head and Neck Cancers at Massachusetts General Hospital, discusses the treatment options now available for patients with iodine-refractory differentiated thyroid cancer (DTC).

Multiple options are available for patients whose thyroid cancer fails to respond to radioiodine therapy. Multikinase inhibitors sorafenib (Nexavar) and lenvatinib (Lenvima) are approved for patients with iodine-refractory DTC. Additionally, entrectinib (Rozlytrek) and larotrectinib (Vitrakvi) are approved for patients with an NTRK fusion alteration, while pralsetinib (Gavreto) and selpercatinib (Retevmo) are approved for patients with advanced or metastatic disease with a RET fusion.

Wirth says that there is no head-to-head comparison for multikinase inhibitors and NTRK inhibitors. Larotrectinib is a promising option for those with NTRK fusions due to its high overall response rate of 75% in 3 pooled single-arm trials, and it is approved for any line of treatment, so it can be given before a multikinase inhibitor.

Larotrectinib has shown efficacy in patients who previously received a multikinase inhibitor, but Wirth says it is not known whether acquired resistance to larotrectinib will reduce the efficacy of multikinase inhibitors given after larotrectinib, so the optimal sequencing following larotrectinib is not clear.

TRANSCRIPTION:

0:08 | In patients with radioiodine-refractory progressive DTC, we now have a number of treatment options available that are FDA approved. Sorafenib and lenvatinib are 2 multikinase inhibitors that are both FDA approved for that patient population. And then we have the NTRK-directed therapies for NTRK-fusion positive disease and now we also have RET-directed therapies for RET fusion-positive disease. So, for a patient with NTRK-fusion positive iodine-refractory DTC, should we use a drug like larotrectinib first, or should we use a multikinase inhibitor like lenvatinib first? We don't have a head-to-head comparison. I can't tell you for sure what the right answer is.

1:00 | However, the FDA approval of larotrectinib is line-agnostic, which means that it can be used in the [United States] in the first-line setting. And so I think we need to make the decisions on a case-by-case basis and discussion with the patient. But I think in general, because the response rates are really as high as they are, and because the larotrectinib is as tolerable as it is, it usually makes most sense to start with larotrectinib, rather than starting with a multikinase inhibitor.

1:37 | The one caveat that I would say…is that we know that larotrectinib can work well in patients that have previously received a [multikinase inhibitor] like lenvatinib or sorafenib. But what we don't know is if patients can respond well to larotrectinib but ultimately, if they develop acquired resistance to larotrectinib, can we then get benefit with a multikinase inhibitor like lenvatinib? So there's a sequencing question that we don't quite know the answer to.