Roundtable Discussion: Perez Explores Therapeutic Options in RET-Mutated NSCLC

Molecular testing and treatment decisions. can vary for patients with non–small cell lung cancer (NSCLC). Cesar A. Perez, MD, Head and Neck Medical Oncology lead and medical director of Utilization Review at the Sylvester Comprehensive Cancer Center of the University of Miami and a group of other physicians discussed next steps in care for a patients with NSCLC whose molecular test results revealed a RET mutation.

PEREZ: We’ll start in a general discussion, and I would like to know your opinion on molecular testing. How do you order the molecular panel testing for our patients with lung cancer? How do you start ordering the genomic testing? What exactly do you do for tissue, for testing, initially, and for sequencing?

SALZBERG: If there’s sufficient tissue, I’ll send out for next-generation sequencing [NGS] of the original biopsy. I’ll send a Guardant [Health test] at the same time, primarily because it comes back quicker. There’s heterogeneity between the tissue biopsy and blood-based biopsy.PEREZ: You have molecular testing side-by-side, right?

SALZBERG: I do.PEREZ: They both say the same thing. Anyone else? What do you guys think? Everyone does circulating tumor DNA [ctDNA] testing? Is there anyone who doesn’t believe in plasma testing who wants to comment?

AZZI: I believe in plasma testing and also plasma monitoring, now, for response assessments. That’s what I do. But I do a hybrid between the companies right now. I’ll do the Guardant for the initial testing, and then I’ll send my NGS to Natera and then use the Signatera later for tracking.

PEREZ: That’s interesting. I think ctDNA has very strong data. The tracking is what is still being studied. It’s interesting what we get when we keep following the plasma ctDNA over time. Do you think access to tissue and insurance issues that you’re having are getting better or worse? What do you guys think about testing?

AZZI: Thankfully, these companies have generous assistance programs, but with private insurance, it’s ridiculous. The testing gets denied all the time either on tissue or on blood, and [certain ones] don’t cover a panel with more than 35 genes, so you have to find a vendor with 35 genes. Otherwise, they’re not going to cover the test, which is ridiculous. There’s no panel of 35.

PEREZ: Most of us want to test more than that, right?

AZZI: It cannot have RNA, by definition; the panel of 35 genes is not going to have RNA signatures….[The test that] meets that definition would be NeoGenomics, which…is a whole mixture of immunohistochemistry and fluorescence in situ hybridization and all that, which is like an inferior technology. They don’t have a real product to offer with 35 genes. You could theoretically limit yourself in lung to 35 genes. There just isn’t a good product out there with 35 genes.

PEREZ: Most of you will wait for molecular results, and some of you will do brain radiotherapy while waiting. There’s no right or wrong answer. Some patients will make their own “decisions,” right? All the options are “thoroughly adequate” except for chemotherapy alone; that probably wouldn’t be a good option.

PEREZ: We hadn’t heard much about RET rearrangement until probably 3 or 4 years ago, and it’s expressing in 1% to 2% of all patients with NSCLC, more commonly adenocarcinomas. Have any of you seen a patient with lung masses, brain metastases, and a [RET rearrangement]?

SANTOS: I have seen patients with RET and my patients have not developed any brain metastases.

PEREZ: No brain metastases, so far. If you found out that a patient has brain metastases, would that change what you do initially in terms of your treatment selection?

SANTOS: Me, personally, no. As we know, [the available] medications have a very good overall response rate in the brain. So, if the patient is asymptomatic, we would go with a targeted therapy.

PEREZ: Are you guys doing MRIs at baseline for any patients with stage IV at screening? Or just with symptomatic patients?

IKPEAZU: It’s the standard of care.

NAKKA: Basically, I do a brain MRI in the screening test before starting treatment.

PEREZ: Most of you guys would choose 1 of the 2 selective RET inhibitors. Selpercatinib [Retevmo] seems to have more preference, pralsetinib [Gavreto] came second, and then vandetanib [Caprelsa] was third. How do you decide which one you are going to use? What drives your selection? If you guys are using a RET inhibitor on front-line [therapy], how come you’re not choosing an immune checkpoint inhibitor? Why not chemotherapy?

IKPEAZU: There are data that patients who have a RET fusion don’t respond very well to an immune checkpoint inhibitor, so you have to keep that in mind before you initiate immune checkpoint inhibitors in these patients. For a patient who is RET fusion positive, my to-go strategy is selpercatinib.

PEREZ: They don’t respond very well [to the] checkpoint inhibitors, those with RET mutations, despite having positive PD-L1. In the NCCN [National Comprehensive Cancer Network] guidelines for NSCLC for RET rearrangementpositive disease, the first-line preferred regimens are both selpercatinib and pralsetinib.¹

Although cabozantinib [Cabometyx] and vandetanib [are considered] useful in certain circumstances, those are considered category 2B. Although cabozantinib [Cometriq] and vandetanib [are considered] useful in certain circumstances; those are considered category 2B.

IKPEAZU: I’m surprised that NCCN guidelines have cabozantinib and vandetanib in there. These are nonspecific RET inhibitors.

PEREZ: They keep changing them, so for now, that’s how they look, but maybe they will change.

IKPEAZU: I think the data [from LIBRETTO-001] are very compelling.…The CNS penetration is also very interesting and very encouraging.² I have a patient right now on selpercatinib, and he’s doing marvelously well. This guy came in on oxygen with a pleural effusion. He is no longer on oxygen; the pleural effusion is gone. He’s been on selpercatinib for about a year now.

PEREZ: It’s certainly very impressive, and it’s what we saw with the EGFR [inhibitors] back in the day—not all these mutations respond that well to these treatments, but selpercatinib [had] very impressive responses. In the CNS subgroup, most of the patients will have at least stable disease. Most of them will respond. What do you guys think about the ARROW trial of pralsetinib? Do you feel it’s also strong or compelling?

IKPEAZU: [They were quality data], including CNS efficacy.³

PEREZ: They were also quite strong data. [Do you use one drug over the other for patients?]

IKPEAZU: I started [a patient] with selpercatinib, so if I have another patient, who knows, I might just put the patient on selpercatinib. I don’t think it’s an error to switch to pralsetinib. They are equally efficacious. It’s just that selpercatinib was the one that was first available, and I prescribed it.

PEREZ: Selpercatinib is what first came to market, and the people can get more used to it initially, but now, they’re both available. Anyone have any other comments?

NAGOVSKI: I haven’t treated a single patient yet, but both agents seem to be active to me and effective. I would probably reach out to one of you guys, experts in the field of lung cancer, before I put my patient on therapy. Other than that, I believe both agents are very active, and maybe it comes down to how familiar and how comfortable you are when you get more experience with one or the other agent.

PEREZ: For sure. Definitely, both agents have very compelling data. Some people are having a hard time choosing. Any issues that you would raise about the COVID-19 pandemic or with either agent? Or has COVID-19 not made much of a difference in which one you choose?

SANTOS: No, no change at all. I would treat [the same way].

PEREZ: With efficacy, do you feel stronger about one or the other, or do you think both probably are similar? It’s just 2 different drugs or maybe 2 different patients? Any difference?

SANTOS: The number of patients in these trials is small. It is understandable. It’s a very rare mutation. Perhaps the issue is going to [present itself] more frequently, when you identify these fusion proteins as a mechanism for [other drugs].…I think that we need to know and understand all the adverse events, and they are going to become more and more important as we move into the future when the patient is said to have resistance.

PEREZ: Definitely. You focus on efficacy; you focus on adverse effects. That’s how you choose your treatment at the end.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer; version 5.2021. Accessed July 7, 2021. https://bit.ly/3yzHWBC}

_{2. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non–small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. doi:10.1056/ NEJMoa2005653}

_{3. Subbiah V, Hu MIN, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion-positive solid tumors. J Clin Oncol. 2020;38(suppl 15):109. doi:10.1200/JCO.2020.38.15_suppl.109}