Up-front Testing Is Imperative for Treatment Decisions in RET+ NSCLC

The use and interpretation of molecular testing to identify RET fusions in patients with EGFR-mutated non–small cell lung cancer (NSCLC) continues to be critical for both the selection of approved RET inhibitors and the development of novel strategies to combat disease resistance mechanisms, according to Deborah B. Doroshow, MD, PhD.

“We have to perform the testing, but we also have to use the results of the testing to guide our management. If we have these terrifically active drugs but we don't give them to eligible patients, we're not helping anybody,” Doroshow said in an interview with OncLive® regarding her presentation on RET fusions in lung cancer at the 24th Annual International Lung Cancer Congress®.

In September 2020, the FDA granted accelerated approval to pralsetinib (Gavreto) for the treatment of adult patients with locally advanced or metastatic NSCLC with a RET gene fusion based on positive efficacy data from the phase 1/2 ARROW trial (NCT03037385).¹ The RET inhibitor selpercatinib (Retevmo) also received accelerated approval in this space in 2020, and was granted regular by the FDA in September 2022. This decision was supported by the phase 1/2 LIBRETTO-001 trial (NCT03157128), which met its primary end point of improved overall response rate and duration of response.²

Both agents were designed to be highly selective, and it greatly improved off-target toxicities compared with prior multikinase inhibitors without sacrificing efficacy.

In the interview, Doroshow expanded on the efficacy and toxicity profiles of pralsetinib and selpercatinib, and how they influence treatment selection for patients with RET fusion–positive tumors. She also provided insight on several areas of ongoing or potential research in lung cancer, including the development of agents for resistant disease and the evaluation of osimertinib combination therapies in the frontline.

Doroshow is an assistant professor of medicine, hematology, and medical oncology at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai ​Hospital, in New York, New York.

OncLive: Could you compare and contrast the use of selective RET inhibitors in the first-line setting for patients with RET fusion–positive lung cancer?

Doroshow: We have 2 FDA-approved, first-line, selective RET inhibitors: pralsetinib and selpercatinib. They're very similar in terms of efficacy and they both have good central nervous system penetration. They [also] both have response rates [of approximately] 70%, and [produce] durable responses in patients [with NSCLC] in the first line and in patients who've received platinum-based chemotherapy.

They do have different toxicity profiles, which is one thing to consider. They both cause things like fatigue, but then have some differences in adverse effects [AEs]. For example, pralsetinib causes more [blood cell] count suppression and selpercatinib causes more [liver enzyme] elevation. They're not identical and are not interchangeable, although they are very similar with respect to efficacy.

In what scenarios might you choose pralsetinib over selpercatinib, or vice versa?

If I had a patient in front of me who had a RET fusion, I would not have a clinical preference. I will say that the first one I ever used was selpercatinib so I've become more comfortable with that agent. There's something to be said for that. [However], there's not any reason to necessarily choose one over the other unless you have a patient who has an elevated liver function test or a low white blood cell count, where you really might want to think about the different toxicity profiles.

What challenges do researchers face when attempting to identify and target resistance mutations or alterations in lung cancer?

[At the meeting], I talked about a second-generation selective RET inhibitor that was presented at ASCO [called KL590586 (A400/EP0031)]. We need to look at inhibitors that are going to address some of the most common types of resistance. Unfortunately, there are no "most common" types. We can see on-target RET alterations, such as G810, in over 10% of those who have resistant disease. In terms of off-target alterations, which can happen in about 40% of patients, there is no dominant type of resistance. We may just need more potent inhibitors that lead to more durable responses. Looking at mechanisms of resistance right now, a lot of the time there's not one specific mechanism that we ought to focus on. It's not like the EGFR world was when we had T790M in [about] half of patients who had resistance, for example.

The potential use of targeted therapy in combination with chemotherapy has become an area of interest in EGFR-mutated lung cancer research. Do you feel this approach has promise in the frontline setting? Why or why not?

I'm not terribly interested in [the potential use of] those combinations upfront. Right now, we know that osimertinib [Tagrisso] plus chemotherapy improved progression-free survival [PFS]. That's not surprising at all, because you've just put together 2 active drugs from different categories. The real question is: does giving the drug now improve survival compared with giving the drug later? It can do that when there's synergy between the 2 drugs or the 2 classes of drugs, or if patients [are unable] to receive a second line of therapy because they're too sick. Those kinds of studies need to look at overall survival [OS] as a primary end point. I don't find PFS terribly helpful. There is room to investigate administering these inhibitors in combination with other potential targeted therapies like anti-MET agents, since we see that 14% of [patients] in a recent retrospective study have MET amplification as a form of resistance. [However], I'm not as excited by the chemotherapy combination studies unless they show an OS benefit.

What has your experience testing for resistance mutations been like in the clinic, and how does the ability to perform a liquid biopsy affect subsequent treatment decision-making?

We [perform] liquid biopsies on everybody. It's very easy, and our nursing team are experts at filling it out and getting it done. We get answers quickly, and that's helpful. [Yet] there are many times when a liquid biopsy does not pick up a driver mutation that we've already seen in tissue. I would prefer to get tissue from everybody, but it depends [on the patient's situation]. Sometimes they don't have safely and easily accessible tissue. Sometimes they're not interested in the biopsy, and I can't fault anyone for that. Sometimes they're too sick to undergo a biopsy. If I can do both, I will. I get answers from liquid [biopsy] rapidly vs scheduling a biopsy and getting a tissue result, but sometimes it's not possible to get tissue.

What are some future avenues for the investigation of RET in the lung cancer space?

One of the things [discussed in my presentation that] I'm most passionate about is a retrospective study. Even though about [75%] of patients in the Flatiron-Foundation Medicine Clinico-Genomics database were being tested for RET alterations, only about 40% of patients who were found to have RET alterations received a first line RET inhibitor. I'd like to see some more work on that follow through happen.

What advice might you give community oncologists when selecting a targeted therapy for patients based on the interpretation of a pathology report?

First of all, I can't imagine how challenging it must be to take care of people with all kinds of cancer. I can barely keep up with lung cancer! If you're not familiar with a new medication, for example, you may not reach for it first [or] you may not be aware that it's starting to be used in the first line. What I do in my practice is ask a lot of questions. I have some fantastic colleagues who enjoy talking about patients and sharing ideas. There is no one way for one person to know everything. Having communities where you can share knowledge and advice is critical to good oncology practice.

References

1. FDA approves pralsetinib for lung cancer with RET gene fusions. FDA. September 4, 2020. Accessed July 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pralsetinib-lung-cancer-ret-gene-fusions
2. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive non-small cell lung cancer. News release. FDA. September 21, 2022. Accessed July 28, 2023.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib