Sequencing Therapies for Advanced Thyroid Cancer After an NTRK Inhibitor

Lori J. Wirth, MD, discusses sequencing therapies for patients with NTRK fusion–positive advanced thyroid cancer.

Lori J. Wirth, MD, associate professor of medicine at Harvard Medical School and medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, discusses sequencing therapies for patients with NTRK fusion–positive advanced thyroid cancer.

Wirth says she would use the NTRK inhibitor larotrectinib (Vitrakvi) as first-line therapy based on its 75% objective response rate (ORR) in clinical trials. Larotrectinib received a tissue-agnostic FDA approval for solid tumors with an NTRK fusion, including in the first line if there is no satisfactory alternative treatment.

However, tumors can develop acquired resistance to NTRK inhibition, so if a patient progressed on larotrectinib, she recommends identifying the mechanism of resistance to find a clinical trial for a second-generation NTRK inhibitor that may prove effective.

Entrectinib (Rozlytrek) is another NTRK inhibitor with the same indication, but it would be less likely to be effective against a tumor that developed resistance to larotrectinib, so it should not be used as second-line therapy, according to Wirth. Another next-line option is a multikinase inhibitor such as lenvatinib (Lenvima), which has shown efficacy in radioiodine-refractory advanced thyroid cancer. However, there are no data on the use of lenvatinib in a patient with acquired resistance to larotrectinib.


0:08 | For patients with NTRK fusion–positive advanced thyroid cancer, generally, I do use larotrectinib in the first line because of the high ORR and very good tolerability. We do know that patients can develop acquired resistance—so they can respond beautifully, but then ultimately begin to develop progression. In patients with acquired resistance, we biopsy the lesion that's growing and do genotyping to see if we can identify the mechanism of acquired resistance. If we have a clinical trial that the patient can enroll on, then we would favor participation in clinical trials because there are second-generation NTRK inhibitors that are being studied now, in the phase 1/phase 2 setting.

If, however, a clinical trial option isn't available, then, in general, I wouldn't turn to another first-generation NTRK inhibitor like entrectinib because we think that the mechanisms of acquired resistance will mean that you can't cross over from larotrectinib to entrectinib and expect any activity with the other drug or vice versa. I think switching over to entrectinib is off the table. But certainly, if a patient is otherwise a candidate for a multikinase inhibitor, I think that that's a reasonable thing to try. I just don't know that we have much data yet on how likely it is that a patient with acquired resistance on larotrectinib would respond to a multikinase inhibitor like lenvatinib, but I'd certainly give lenvatinib a try.