Updates on Biomarker-Directed Therapy for Solid Tumors: Focus on NTRK, RET, and NRG-1 - Episode 13

NRG1 Fusions in Solid Tumors: The CRESTONE Trial

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

Mark Socinski, MD: 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.

Jyoti Patel, MD, FASCO: 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.

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

Benjamin Levy, MD: 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.

Mark Socinski, MD: Does this include NRG1?

Benjamin Levy, MD: 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.

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

Jonathan Trent, MD, PhD: 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.

Mark Socinski, MD: 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?

Lori Wirth, MD: 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.