Mark Socinski, MD: We are going to transition to our next topic; we will be talking about RET and a little about NRG1 fusions. I think Dr Wirth knows about RET in this setting. I am going to ask her to set the stage for the role of RET in oncogenesis.Lori Wirth, MD: Since Ben talked about the history of NTRK in oncology, why don’t I start out by discussing the identification of RET-rearranged in transfection? This was first discovered, I believe, in 1986 by Masahide Takahashi, MD, PhD, in an NIH3T3 cell line. Then 1 year later, Alfredo Fusco, MD, in Italy identified RET fusions in papillary thyroid cancer. Then shortly after that, the RET gene was cloned in patients with familial MEN2A and MEN2B [multiple endocrine neoplasia type 2A and 2B] syndromes, causing as we know medullary thyroid cancer, as well as the other endocrine neoplasias associated with those syndromes. It was not until RET was identified as a fusion driving non–small cell lung cancer that the pharmaceutical industry really got interested in potently inhibiting RET. We did have the multikinase inhibitors like vandetanib, cabozantinib, and others that do have anti-RET activity along with VEGFR2, KDR, EGFR, and so forth.

I think it took the identification of KIF5B RET fusions in non–small cell lung cancer to really turn the spotlight specifically on RET. RET is a juicy target because it is a receptor tyrosine kinase. Interestingly, it does not homodimerize exactly with itself with ligand binding, but there is a GDNF [glial cell line-derived neurotrophic factor] coreceptor that the ligand binds to, and then that coreceptor leads to homodimerization, forming a complex of activated RET. There is signaling, as a result of that, through multiple signaling pathways. RET fusions are, of course, seen in papillary thyroid cancer and other thyroid cancers in the subset of patients with non–small cell lung cancer. They can be rarely identified in other cancers, including pancreatic adenocarcinoma. Then we see RET point mutations, deletions, and a couple of other alterations in the majority of patients with medullary thyroid cancer, whether it’s a germline mutation in MEN2A or MEN2B, or a somatic mutation arising in a sporadic cancer.

Mark Socinski, MD: In that situation I’m under the impression, Lori, that you might see RET mutations in other tumors, but it is really felt to be a driver only in the setting of medullary thyroid cancer. Is that a fair statement?

Lori Wirth, MD: I do think it is a fair statement. Again, I think it is because RET is not necessarily expressed in other tissues. A point mutation is not going to have any sort of oncogenic effect if it is not expressed to begin with.

Mark Socinski, MD: Let’s discuss the impact of fusions and mutations on clinical outcomes. Before we had the real potent, modern-day RET inhibitors, how effective were those drugs, like sunitinib, vandetanib, and cabozantinib, and those other “dirty kinase” treatments, as we call them? What was your experience prior to the modern era?

Lori Wirth, MD: There are MKIs [multikinase inhibitors] that are approved for iodine-refractory differentiated thyroid cancer that have anti-RET activity. There are also MKIs approved for medullary thyroid cancer. There is activity in cases of DTC [differentiated thyroid cancer] whether or not RET fusions are present. There is also good activity in cases of MTC [medullary thyroid cancer] whether or not RET mutations are present. However, at least regarding patients taking cabozantinib who are being treated for medullary thyroid cancer, a subset analysis correlating activity with a specific RET mutation did show that it looked like cabozantinib is more effective in patients who harbor a RET M918T mutation, which is in the tyrosine kinase domain. There is even a survival benefit that was seen in that particular patient population.

It is not too surprising, because in MTC, there is a really interesting genotype-phenotype correlation. The various RET mutations do cause various degrees of aggressiveness of the cancer. In the familial syndromes, we see not just aggressiveness in terms of the age of onset of medullary thyroid cancer, but also in the risk of developing the other endocrine neoplasias like hyperparathyroidism and pheochromocytomas.

Mark Socinski, MD: I’m under the impression that, at least in thyroid cancer, the germline issues are more commonly seen than the somatic mutations. Is that fair?

Lori Wirth, MD: Not quite; about 25% of medullary thyroid cancers will be seen in patients who have MEN2A or MEN2B. They all have germline RET mutations; MEN2A germline mutations are more common because MEN2B is just very aggressive. Of the 75% of patients who do not have the hereditary MEN2A or 2B syndromes, approximately 60% will have somatic RET mutations driving their MTC. Overall, the somatic RET mutations are more common in MTC because sporadic MTC is more common. Getting back to tumor testing and so forth, this germline versus somatic mutation adds a whole other level of confusion regarding how to test. One thing to point out is that we are talking mostly about NGS [next-generation sequencing] testing in today’s program, but for patients with medullary thyroid cancer, we absolutely have to make sure that those patients do not have a germline RET mutation. It has implications not only for their individual health and care, but it also has implications for all of their first-degree family members.

Mark Socinski, MD: Thank you. Ben, I want to give you the microphone for a second here, but I am going to limit your comments. When I first went to UPMC [University of Pittsburgh Medical Center], in 2011, or shortly thereafter, we were testing for RET. Occasionally we did find it in patients with lung cancer. In my experience with the drugs we mentioned before, like cabozantinib and sunitinib, the multikinase inhibitors have a lot of off-target effects and were not particularly active in the RET fusion-positive lung cancer population. I am wondering if you had a similar experience. I do not want you to talk about the newer agents selpercatinib or pralsetinib because I want to give Lori the stage for that in a second. But there has been such a change in our ability to target this alteration that I want to give people a sense of what it was like prior to the modern era.

Benjamin Levy, MD: These drugs have already been bounced around during the discussion, and we have tried them in a lot of these tumors where we have identified some sort of RET alteration. Vandetanib, cabozantinib, sorafenib, sunitinib—these were all drugs that may have had some RET activity. Now that we have these drugs, they do not elicit the meaningful activity that we are now seeing with these newer drugs, and they are not as well tolerated. I think this has been a win to have these new drugs, but certainly, dirty TKIs [tyrosine kinase inhibitors] are just that. They are not that selective; the depth of response and meaningful response are not as common, and there is more toxicity to deal with. I can recall several experiences with some of these drugs where you are just not getting a lot of activity out of what you think may work. It is an oral therapy. A lot of patients may think, “I am not getting chemotherapy, so maybe it will work,” but my experience with these treatments has not been as favorable as with the newer drugs.

TRANSCRIPT EDITED FOR CLARITY