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<i>RET</i>-Altered Thyroid Cancer
Targeting RET in Advanced Thyroid Cancers

Released: November 04, 2020

Expiration: November 03, 2021

Lori J. Wirth
Lori J. Wirth, MD
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The treatment landscape for patients with thyroid cancers has expanded rapidly in the era of precision medicine. With the recent approval of the selective RET kinase inhibitor selpercatinib, as well as the anticipated approval of a second RET inhibitor, pralsetinib, a new standard of care has arrived for patients with RET-altered thyroid cancers.

RET Alterations in Thyroid Cancers
RET is altered in 2 important, different ways in thyroid cancer: (1) activating RET mutations, seen in the majority of medullary thyroid cancers (MTC); and (2) activating RET fusions, seen in a minority of papillary and other thyroid cancers. 

Among MTCs, there are familial MTCs characterized by the presence of germline RET mutations in all affected patients, and there are sporadic MTCs, in which approximately 60% of patients harbor a somatic activating RET mutation. RET mutations that give rise to MTC typically occur in the tyrosine kinase domain, particularly RETM918T, or in the extracellular cysteine‑rich domain of the receptor, both of which lead to constitutive activation of the RET tyrosine kinase.

RET fusions are most commonly found in papillary thyroid cancers, accounting for approximately 10% of all papillary thyroid cancers, but with a higher incidence of approximately 30% in pediatric and young adults. Although uncommon, RET fusions are also seen in poorly differentiated thyroid cancer and even anaplastic thyroid cancer. There are numerous potential 5’ fusion partners with RET in thyroid cancer, but the 2 most common are CCDC6 and NCOA4. 

Standard Treatment Options for MTC
Many patients diagnosed with MTC will have good outcomes with just surgical management. This cancer has a variable natural history, with disease in some patients progressing slowly over time and, in others, more rapidly. For those patients who eventually develop locally recurrent unresectable and/or distant metastatic disease to the extent they require systemic treatment, we historically have had 2 drugs in our arsenal: the multikinase inhibitors vandetanib and cabozantinib. Both of these agents are active against MTC in terms of improved responses and prolonged PFS, but they also engender a significant amount of toxicity due to off-target effects. Common adverse events include fatigue, diarrhea, weight loss, and hypertension.

Approval of Selpercatinib for RET-Altered Thyroid Cancer
However, we now have selpercatinib, the first RET‑specific kinase inhibitor to be approved by the FDA for the treatment of patients with thyroid cancer harboring RET alterations, including:

  • Adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant MTC who require systemic therapy, and
  • Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory.

Unlike cabozantinib and vandetanib, selpercatinib is specific for the RET kinase, which leads to increased potency and fewer off‑target adverse events as compared with the multikinase inhibitors.

LIBRETTO‑001: Selpercatinib in RET-Altered Solid Tumors
The approval of selpercatinib for thyroid cancers is based on data from the multicenter, open-label phase I/II LIBRETTO‑001 study. In this trial, patients with RET-altered, locally advanced/metastatic solid tumors received selpercatinib, with the primary endpoint of ORR.

There were 2 cohorts of patients with MTC, both of which experienced significant antitumor activity with selpercatinib. The first cohort comprised patients who had received previous vandetanib and/or cabozantinib (n = 55). Selpercatinib achieved an ORR of 69% and a 1‑year PFS rate of 82% in these patients; at the time of data cutoff, median duration of response and median PFS had not been reached. The second cohort were patients who had not previously received either vandetanib or cabozantinib (n = 88). The ORR in this cohort was 73%, with a 1‑year PFS rate of 92%. Again, the median duration of response and PFS had not yet been reached, with fewer than 10% of the total number of events having occurred. 

The trial also enrolled 19 patients with RET fusion–positive thyroid cancers, including papillary thyroid cancer and 2 patients with anaplastic thyroid cancer. In these patients, we saw an ORR of 79% and a 1‑year PFS rate of 64% with selpercatinib, and yet again, the median PFS and duration of response had not been reached. Of importance, 1 of the 2 patients with anaplastic thyroid cancer had a response.

In addition to potent and durable efficacy, selpercatinib demonstrated a favorable toxicity profile in LIBRETTO-001, with mostly grade 1/2 treatment-related adverse events. The treatment was well tolerated, with fewer grade 3/4 adverse events as compared with our historical multikinase inhibitor options and fewer patients requiring dose reductions (30% vs 35% for vandetanib and 76% for cabozantinib) or discontinuing (2% vs 12% for vandetanib and 16% for cabozantinib) due to toxicity. Finally, there were no treatment‑related deaths on this study.

A common adverse event of MTC is diarrhea caused by the calcitonin secretion that these cancers are famous for. Indeed, the majority of patients with MTC in the LIBRETTO‑001 trial had significant diarrhea at baseline. When we reviewed patient‑reported outcomes among this cohort for a report at ESMO 2020, we saw that most patients had substantial improvement in diarrhea after initiating selpercatinib, and the improvement was sustained over the duration of treatment. 

In summary, selpercatinib is a potent, safe, and well-tolerated anticancer drug that leads to significant improvement in disease status for patients with RET alteration–positive advanced thyroid cancer as well as improvement in their quality of life, especially as compared with other available therapies for relapsed disease.  

Clinical Pearls for Integrating Selpercatinib Into Practice

Testing for RET Alterations
Now that we have such an efficacious and safe drug in selpercatinib for the treatment of our patients with advanced RET alteration–positive thyroid cancer who require systemic therapy, the next hurdle is to increase awareness for testing of our patients for RET alterations as the new standard of care.

Genotyping in MTC can be confusing. Until recently, we had primarily been testing patients with MTC via a blood test for the presence of germline RET mutations indicative of a familial syndrome, which has important implications for first degree family members. By contrast, now that we have a RET‑specific inhibitor, we must test for the presence of a RET mutation, whether it is a germline mutation or a somatic mutation. Detection of somatic RET mutations typically requires testing of the tumor specimen by next-generation sequencing that is separate from germline mutational testing.

For patients with iodine-refractory, nonmedullary thyroid cancer, it has not been a standard of care to do any genetic testing. However, now with approval by the FDA of targeted therapies for patients with advanced iodine‑refractory thyroid cancer harboring NTRK or RET fusions, there is a clear need to look for driver alterations in these patients. Furthermore, because both NTRK and RET have numerous different fusion partners, it is important for the oncologists ordering the tests to select testing methods capable of detecting all of the known fusions vs only the most common ones.

Monitoring for Treatment-Related Adverse Events
Although selpercatinib is generally well tolerated, some patients can experience QTc prolongation, an uncommon but serious treatment‑related adverse event that clinicians should be familiar with. Patients receiving selpercatinib should have baseline ECGs followed by routine ECGs after starting therapy, and those receiving concomitant drugs known to prolong QTc interval should receive more frequent monitoring. Transaminitis is another important treatment‑related adverse event with selpercatinib. Liver function testing should be performed before and during treatment as part of routine blood test monitoring.

Improvements in Tumor Markers
In LIBRETTO-001, there was an improvement in classical thyroid tumor markers that generally correlated with response to selpercatinib, including decreases in calcitonin and CEA typically measured in MTC, and decreases in thyroglobulin in those with papillary thyroid cancers. When treating patients with selpercatinib, we can anticipate seeing these improvements among patients with a clinical response.

Acquired Resistance and Progression on RET-Targeted Therapy
Similar to other gene‑specific treatment settings, some patients with thyroid cancer have already developed acquired resistance to selpercatinib and pralsetinib. The mechanisms of this acquired resistance to RET-specific therapy are currently under investigation, and second-generation RET inhibitors are in clinical trials to evaluate their efficacy in these patients. Although the optimal option for those who progress on selpercatinib would be a clinical trial of one of these investigational therapies, another option for patients who progressed on first-line selpercatinib would be to treat with vandetanib or cabozantinib (for MTC) or lenvatinib or sorafenib (for differentiated thyroid cancer). Finally, a common question is whether patients who have progressed on selpercatinib could respond to pralsetinib. I think it is unlikely, as the 2 drugs are similar enough that acquired resistance to one would likely translate to resistance to the other.

Closing Remarks
In closing, following in the footsteps of metastatic non‑small-cell lung cancer, advanced thyroid cancer has now become a poster child for molecularly driven treatment. With the approval of selpercatinib and the anticipated approval of a second RET‑specific drug, pralsetinib, a new era of gene‑specific therapy has emerged for this suite of diseases.

Your Thoughts?
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