Selpercatinib Continues to Progress RET Fusion+ Thyroid Cancer Treatment

Marcia S. Brose, MD, PhD, FASCO

The development of selpercatinib (Retevmo) for the treatment of various thyroid cancer groups has been a strong addition to the field, according to Marcia S. Brose, MD, PhD, FASCO. Three trials in the LIBRETTO program have reported positive results (LIBRETTO-001, NCT03157128; LIBRETTO-121, NCT03899792; LIBRETTO-321, NCT04280081) and another trial is expected to read out later this year (LIBRETTO-531, NCT04211337).

Selpercatinib, a selective RET kinase inhibitor, is an FDA-approved therapy for patients with RET fusion-positive advanced or metastatic solid tumors, including thyroid cancers. Both its thyroid-specific and tumor agnostic indications were based on results from the LIBRETTO-001 study. The drug was the first therapy approved to target RET gene alterations.

“My hope is that it will continue to fulfill the promise that we've seen in both studies, and that patients will get access to it, and that the results will continue,” said Brose, professor in the Department of Medical Oncology Sidney Kimmel Medical College Thomas Jefferson University, professor and vice chair in the Department of Medical Oncology Jefferson Northeast, chief of Cancer Services, Sidney Kimmel Cancer Center-Jefferson Northeast, associate director of Community Based Clinical Research, and SKCC chair of Hematology/Oncology, Jefferson Torresdale Hospital, in an interview with Targeted Oncology™

In LIBRETTO-001, selpercatinib achieved robust and durable responses in adult patients with locally advanced or metastatic, RET fusion-positive solid tumors. According to a trial update from 45 patients with various solid tumors published in the Journal of Clinical Oncology, selpercatinib achieved an objective response rate of 44% (95% CI, 29%-60%), which included complete responses in 2 patients, partial response in 16, and stable disease in 8. The clinical benefit rate observed was 63%.

The time to response shown with selpercatinib was 1.9 months, and the median duration of response was 24.5 months (95% CI, 9.2 months to not evaluable). Selpercatinib also demonstrated a median progression-free survival of 13.2 months (95% CI, 7.4-26.2 months).

The study did not identify any new safety signals for selpercatinib. Grade 5 adverse events (AEs) occurred in 3 patients; these AEs led to treatment discontinuation in 4 patients.

In the interview, Brose discussed the impact of selpercatinib in thyroid cancer, and what to expect from the drug in the future.

TARGETED ONCOLOGY: Can you talk about the LIBRETTO program and what strides have been made because of the LIBRETTO studies?

Brose: There are 2 types of thyroid cancer that have alterations in the gene called RET medullary thyroid cancer. They're quite common and can be in over 50%. Those are usually point mutations. Half of those patients may have it because it was hereditary and the other half had, what's called ‘sporadic just showed up in the cancer.’ There's another up to 20% of patients with differentiated thyroid cancer who have RET fusions. In both medullary thyroid cancer, the point mutations and the fusions with differentiated thyroid cancer, RET can be upregulated.

In the first trial, which was LIBRETTO-001, we looked at both groups and showed that if we use the selective RET inhibitor selpercatinib, we got very nice responses. Patients were able to maintain their responses for extended periods of time. We already had other agents approved for medullary thyroid cancer and differentiated thyroid cancer called multikinase inhibitors. They're a little less specific, their primary activity is VEGF receptor inhibition, but they also hit RET. The question was, if we have a very selective inhibitor, is that better? Is it better to start with that or the multikinase inhibitors?

We only knew from the LIBRETTO-001 trial that these seem to be fairly well-tolerated. Selpercatinib still has [adverse] effects, but it didn't seem to be quite to the degree that we had seen with some of the multikinase inhibitors like either cabozantinib [Cabometyx] and vanndetanib [Caprelsa].

In the case of medullary thyroid cancer or lenvatinib [Lenvima], sorafenib [Nexavar], and now cabozantinib, in the case of differentiated thyroid cancer. Then the question became, are we better off being selective or not?

What is your hope for the future of selpercatinib in advanced or metastatic RET-mutant thyroid cancer?

It already is FDA-approved for these patients. My hope is that it will continue to fulfill the promise that we've seen in both studies, and that patients will get access to it, and that the results will continue. I also hope that we will continue to see strong results, and that we won't be disappointed in any way down the line. I don't anticipate that. I think this is probably one of the best studied drugs. It was thoroughly studied because a lot of times, when a company gets FDA approval, they don't necessarily get such a robust amount of data. A good example of that is the dabrafenib [Tafinlar] study. Dabrafenib was approved tumor agnostically, but in thyroid cancer, the data were poor.

In this case, selpercatinib did get studied in a robust phase 3 study with appropriate controls. I think this is data that we're going to be able to count on for years to come. I hope that most people will get educated quickly, because I do think that this is a paradigm shift for the patients, and an important one. The other thing I hope that it will do, as somebody who specializes in personalized medicine, is bring to everybody's attention the importance of getting complete genetic analysis of patients upfront. If we know about these mutations, if we're going to treat them in the first-line, we have to know that those mutations exist before we start. It needs to be that we go in the direction of all patients who are not cured otherwise by surgery, that everybody who has residual disease in any way we get genetics on those patients, and we find out because this is this is an opportunity for these patients we wouldn't want to miss.

Getting that testing message out is probably the next hurdle, but I think it’s going to get easier as we get more data like what we got from LIBRETTO-531.

What are you hopes for approaching treatment of advanced or metastatic RET-mutant thyroid cancer in the future?

We've gotten a little bit spoiled with the results from selpercatinib, and I think that there's a hope that we often can anticipate. This is a class of drugs that we've seen and used in lung cancer, melanomas, thyroid cancer, and many other cancers. We can already predict often how the resistance develops to these agents.

I think the next stage for the patients who have mutations is to see if there are, again, ways that we can target those mutations specifically, in a way that's refined with low [adverse] effects and good results. Also, I hope we continue this sort of line of successful therapies for the patients who have mutations. That’s number 1.

Number 2, there are mutations that are very common, like KRAS, and unlike KRAS, which we have now lots of inhibitors for, I would love to see an HRAS inhibitor that we can give to those patients, because they tend to not do as well. HRAS mutations are pretty prevalent.

I think we have some more targets we need to go after, and we can follow-up on patients who have resistance. Now interestingly, we know of that happening in lung cancer because they don't get quite as long a progression-free survival as they got with selpercatinib. There's already some work being done, and most of the patients [with] lung cancer can be studied in that way. Interestingly, even from LIBRETTO-001, many of our patients from that first trial are still responding 3 or 4 years later, so we haven't needed to study it or even had the patience to study the resistance mechanisms yet, but we were starting to see them now. We hope that we're going to have good, targeted therapy for them as well.

The targeted of TRK is any interesting story as well. Again, in differentiated thyroid cancer, TRK fusions are not very common, but larotrectinib has been a homerun for those patients. The fact that we now have TRK fusion, and RET fusion, and RET point mutation, all of these probably need to be treated in the first-line with this specific therapy.

I think it goes to say that we don’t want to just test somebody for RET by itself. We need to do broad testing. When we do test people up front, we should do a panel so that we get all the possibly targeted therapies and then also uncover additional ones that might be useful later. Also, at the time of resistance, we should do another panel. Sometimes people develop resistance to that specific molecule. Like in the case of RET, the mutation for the resistance would be in the RET gene, but sometimes they develop resistance by having a mutation in another pathway. It is important to still do a panel test even at the time of resistance. Sometimes, there are more than 1 pathway involved.

_REFERENCES:

_{Subbiah V, Wolf J, Konda B, et al. Tumor agnostic efficacy of selpercatinib in patients with RET fusion+ solid tumors: A global, multicenter, registrational trial update (LIBRETTO-001). J Clin Oncol. 2022;40(16): 3094. Published June 2, 2022. doi:10.1200/JCO.2022.40.16_suppl.3094}