Pralsetinib Approval Expands Options for RET-Positive Thyroid Cancers

The treatment landscape in thyroid cancer now includes 2 therapies specifically for patients whose tumors harbor RET alterations. The FDA granted accelerated approval to pralsetinib (Gavreto) on December 1, 2020, for patients 12 years and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy and those with RET fusion– positive thyroid cancer who need systemic therapy and are refractory to prior radioactive iodine therapy, if appropriate.^1,2

The decision represents an expanded indication for pralsetinib, which gained its initial FDA approval in September 2020 for adults with metastatic RET fusion–positive non–small cell lung cancer (NSCLC). In May 2020, selpercatinib (Retevmo) became the first RET-specific inhibitor approved for similar RET-altered thyroid and NSCLC indications.³

The latest pralsetinib approval was based on data from the multicenter, open-label phase 1/2 ARROW trial (NCT03037385), in which the agent was evaluated in patients with RET-mutated MTC; thyroid cancer and NSCLC with RET fusions; and other RET-altered solid tumors.

In MTC, pralsetinib induced an overall response rate (ORR) of 60% (95% CI, 46%-73%) among 55 patients with metastatic RET-mutant disease who had received prior cabozantinib (Cometriq/Cabometyx), vandetanib (Caprelsa), or both. The ORR was higher at 66% (95% CI, 46%-82%) among 29 patients with RET-mutant MTC treated with pralsetinib who did not receive previous treatment with cabozantinib or vandetanib.

Among 9 patients with RET fusion–positive thyroid cancer that was also refractory to radioactive iodine, the ORR was 89% (95% CI, 52%-100%) with pralsetinib.

In an interview with OncLive^®, Lori J. Wirth, MD, a leading investigator into pralsetinib, discussed the potential impact of the drug on the thyroid cancer treatment landscape. Wirth is medical director of the Center for Head and Neck Cancers and the Elizabeth and Michael Ruane Chair of Oncology at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: What is most significant about the response data in patients with MTC in the ARROW trial?

Wirth: What’s noteworthy about the data on pralsetinib and patients with RET-mutated MTC is that the drug works really well. The response rate of 60% in patients who had been previously treated with vandetanib and/or cabozantinib is really good in terms of activity. And then the response rates were even higher in patients who had not been previously treated, although that was a smaller group of patients.

The other thing to add about the efficacy of pralsetinib is that not only are we seeing high response rates, but the responses are very durable. So far, the data show that we haven’t yet reached the median duration of response or the median progression-free survival [PFS] in these patients.

How do responses with pralsetinib compare with what you see with standard treatment?

The standard treatments, vandetanib and cabozantinib, are pretty good drugs in MTC in terms of efficacy. Particularly in the vandetanib trial [study D4200C00058; NCT00410761], the response rate exceeded 40%. As of the reporting of that trial,the median PFS had not yet been met, meaning that those patients were having durable responses. We can also see very durable responses with vandetanib and cabozantinib in MTC.

However, the response rates that we’re seeing with RET-specific drugs are higher, and the RET-specific drugs are very well tolerated overall. I don’t know if we’re going to end up seeing, once the data are mature, that the efficacy lasts longer with these RET-specific inhibitors than with the nonspecific multikinase inhibitors. That remains to be seen. But among the differences in terms of the treatment and the durability, and the idea that patients are on these therapies for many months, is that the toll that the adverse effect profile takes on the patient overall seems to be less with the RET-specific inhibitors.

What mechanisms does pralsetinib employ to block oncogenic RET activity?

Pralsetinib was designed to be a small molecule inhibitor of the RET receptor tyrosine kinase. The drug binds in the kinase domain and blocks the kinase activity. In MTC, RET is activated primarily by point mutations. In NSCLC and in a subset of follicular-derived thyroid cancers, RET is activated by fusions. It’s the fusions that lead to expression of the kinase and activate constituent activation of the kinase.

Pralsetinib was designed to inhibit the wild-type RET kinase that’s present in those fusion molecules, as well as all of the known mutant RET kinases that we see across various patients with MTC. The drug was designed to be as specific for the RET kinase as possible and to minimize the inhibition of other similar kinases such as VEGR2.

What unanswered questions need to be addressed in the further development of pralsetinib?

With MTC, many patients have relatively indolent disease that grows very slowly and they may be asymptomatic. So an important question is: Is it better to hold off and wait to initiate therapy until patients have more advanced disease? Or is treatment earlier in the course of illness better?

Unfortunately, we have to expect that pralsetinib is not going to work forever in most patients with metastatic MTC and that we will likely see patients eventually progress and develop acquired resistance. We still need to understand what the mechanisms of acquired resistance will be so that the next generation of treatments for these RET-driven cancers can be designed and studied.

References

1. FDA approves pralsetinib for RET-altered thyroid cancers. FDA. December 1, 2020. Accessed December 21, 2020. https://bit.ly/3lv59xP
2. Genentech announces FDA approval of Gavreto (pralsetinib) for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer. News release. Genentech; September 4, 2020. Accessed December 21, 2020. https://bwnews.pr/2QWJ4LM
3. Lilly receives U.S. FDA approval for Retevmo (selpercatinib), the first therapy specifically for patients with advanced RET-driven lung and thyroid cancers. News release. Eli Lilly and Company; May 8, 2020. Accessed January 11, 2021. https://bit.ly/35vCq71