 Before we close, I want to talk for a couple of minutes about NRG1 fusions. This is a fusion of the neuregulin 1 gene; these are rare tumors. They do occur in less than 0.5% of many solid tumors, including lung, breast, ovarian, colorectal, pancreatic, and gallbladder tumors and sarcomas. This is primarily a fusion protein that retains an active EGF-like domain and drives proliferation through aberrant HER3 activation. Like most drivers, it is typically mutually exclusive of other drivers. We do have experience with a monoclonal antibody, selumetinib, which blocks the HER3 dimerization as well as HER3 dimerization with other HER family members. There has been a little activity, or a little data presented. What I am familiar with mostly is the NRG1 fusion–positive GI [gastrointestinal] tumors in which there have been a number of responses quite early in the drug development. There is an ongoing trial called CRESTONE, which is looking at a number of cohorts that express NRG1 fusions in this setting. With that background, is anyone seeing this in lung cancer? Jyoti, you are shaking your head yes. Do tell.

 We have picked up a couple of these patients with this NRG1 fusion, and we have been enrolling—we have CRESTONE open as well as the Tarlox trials—trials testing tarloxotinib, which is an epoxy-activated EGFR TKI [tyrosine kinase inhibitor]. There is a cohort of patients with that experience as well as a few patients that we are starting to screen for CRESTONE. These are the early days in terms of activity. Our patients with lung cancer include nonsmokers, young patients, and Asian patients. There is the enriched population of people you would treat with a fusion. Patients, historically and often, have been treated with afatinib off-label with high toxicity and low efficacy, so we will see. Certainly, there has been some early activity in our practice, but there have been really small numbers.

 Ben, have any been identified in the Hopkins practice [Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins]?

 No, I don’t think we’ve identified 1 across the board. Keep in mind that we just moved to a fusion panel about a year ago.

 It does. It’s an important alteration. It’s extremely rare, but there may be some tip-offs, histologically, that may clue you in. Some of the data would suggest that mucinous adenocarcinoma [MAC] is a subtype that may be more likely to harbor these, at least based on retrospective analysis. Yes, it is a rare fusion. We are weaving another story, certainly not chapter 1, 2, and 3 of the targeted therapy story—maybe it’s an appendix—but it’s something we’re going to have to routinely identify because there will be some novel therapies coming down the pike that will elicit meaningful activity. Afatinib, as Jyoti mentioned, does have some case reports. The response to some of the case reports is modest, but this is a new alteration that we’ll need to keep in mind when we start routinely testing or when we continue to routinely test our patients.

 Jonathan, when treating sarcoma, do you have any experience with the NRG1 fusions in your center [Sylvester Comprehensive Cancer Center]?

 What I can tell you is that it’s very rare. I have not seen any patients at our center with this. If we are looking in the published literature, then there has been a reported rate of 0.2%, or 1 of 620 patients who were tested. It is very rare, as far as I can tell, in sarcoma. This goes back to our biomarker testing that we discussed earlier today, and the fishing analogy: We are not going to find these if we do not look, so we just have to continue looking. We will find them.

 Yes, at least we have some agents—even though they are early in development—that look as if they clearly have activity. That’s certainly something to build on. Lori, any comments here in the NRG1 space?

 Living in the Boston area, I am a big lobster aficionado and I am trying to figure out how that big fishing net can incorporate lobsters in it—how can I do this for my analogies? In the same way that lobster really is exquisitely delicious, we do see some exquisitely delicious responses when we are using our gene-specific therapies for our individual patients, and those responses really are life-altering for our patients. It’s just phenomenal, so the more genotyping that we’re doing with broad-based panels that can identify these mutations, amplifications, and fusions, the more patients who will be benefiting in the long term.

Videos

Dr Mark Socinski describes the design and findings of the CRESTONE trial. 

NRG1 Fusions in Solid Tumors: The CRESTONE Trial

Lori, talk to us about the LIBRETTO-001 trial. It obviously changed our world, at least in the realm of lung cancer treatment, from the 

 fusion point of view. Talk us through the design and so forth.

One thing I want to comment on is that, interestingly, the dirty kinases like vandetanib used in MTC [medullary thyroid cancer] have much better activity than in 

fusion non–small cell lung cancer, which is such a curious thing. I do not know why that is, but we can see really good responses with both vandetanib and cabozantinib in patients with MTC. However, we do now have specific inhibitors. Selpercatinib was designed along the same lines as larotrectinib, to potently and specifically inhibit just the RET kinase as much as possible and have as little off-RET inhibition as possible. It was also particularly designed to have as little KDR, VEGFR2 activity as possible, with the idea that with the MKIs [multikinase inhibitors] that do have RET activity, that off-target toxicity not only causes a lot of adverse effects, but it also limits the dose escalation you can get. So you cannot get really potent RET inhibition because of the dose limitation factors of the other kinase inhibitors.

Selpercatinib was designed just to hit RET as hard and as specifically as possible. Pralsetinib was designed similarly. Selpercatinib was also designed to inhibit all of the 

 fusions that we see in non–small cell lung cancer and other cancers. It was designed to inhibit all of the known 

 mutations seen in medullary thyroid cancer. Then it was also designed to head off acquired gatekeeper resistance mutations at the codon V804, which was hypothesized to account for acquired resistance. Subsequently, that was shown in several patients who were treated with cabozantinib or vandetanib and then developed resistance. The LIBRETTO-001 trial was a phase 1/2 trial that enrolled patients with 

-altered cancers. There were several different cohorts, including patients with non–small cell lung cancer that had been previously treated, and non–small cell lung cancer with 

 fusions that had not been previously treated. There were 3 thyroid cancer cohorts. The first thyroid cancer cohort included patients with 

-mutated MTC who had previously received either cabozantinib, vandetanib, or both. Then there was a cohort of patients with 

-mutated MTC who had received neither cabozantinib nor vandetanib. There was also a smaller cohort of patients with 

 fusions and advanced thyroid cancer who had been previously treated.

There were 2 separate publications in 

. The lung publication reported on the primary analysis set of all of the consecutively enrolled patients with lung cancer who had been previously treated. Then we did the same with the thyroid cancer publication. The primary analysis set concerned patients with 

mutated MTC who had previously been treated with cabozantinib, vandetanib, or both. In that primary analysis set of patients with medullary thyroid cancer who had been previously treated, the overall response rate was 69%. When we looked at patients who hadn’t received prior vandetanib or cabozantinib, the overall response rate for that patient population was 73%. In that smaller group of patients with advanced 

 fusion thyroid cancer, their overall response rate was 79%. These responses are all very durable. In the primary analysis set, the median duration of response and median PFS [progression-free survival] were not yet reached by the time of the data maturity for the publications. In terms of non–small cell lung cancer, we see similar degrees of activity; the previously treated 

 fusion cohort had an overall response rate of 64%, with a median duration of response of 17.5 months.

There was an 85% overall response rate in patients who had not been previously treated. In terms of safety, we see primarily grade 1 and 2 adverse events, and these are reversible. There are some treatment-related grade 3 or 4 adverse events that we observed, the most common of which included hypertension, transaminitis, and diarrhea. A small number of patients had QTc [corrected QT interval] prolongation; a couple of patients had grade 3 QTc prolongation. That is certainly something of which to be aware. Overall, however, selpercatinib is very well tolerated. One of the ways we can specifically take a look at tolerability in our patient population with thyroid cancer is by analyzing the frequency of dose discontinuation. With the other multikinase inhibitors, we often see rates of dose discontinuation of 15% to 20% of patients in the trials who have thyroid cancer. With selpercatinib, only 2% of patients had to have dose discontinuations due to treatment-related adverse events.

One of the questions I have had about selpercatinib concerns how much VEGF effect it may have. I cannot remember, what was the grade 3 hypertension rate? It was not insignificant, if I remember correctly.

Yes, it was 11% or 17%, or something like that.

I think it is about 11%, if I am remembering correctly. S. Mike Rothenberg, MD, PhD, is a friend of mine who was involved in the development of selpercatinib early on; he would say, “There’s definitely a little tickle of KDR there.” So we are seeing some off-target VEGFR2 activity, but certainly, it is nothing compared to our other friends we have discussed.

Lori Wirth, MD, reviews the phase 1/2 LIBRETTO-001 trial. 

Mark A. Socinski, MD, Advent Health Cancer Institute

Articles

NRG1 Fusions in Solid Tumors: The CRESTONE Trial

Tumor Agnostic RET Inhibition: The LIBRETTO-001 Trial