Roundtable Discussion: Brose Explores Selpercatinib and Pralsetinib in MTC

Marcia S. Brose, MD, PhD

Both selpercatinib (Retevmo) and pralsetinib (Gavreto) are FDA-approved therapies for RET-altered medullary thyroid cancer. The research supporting both of these agents and the experience with their use in clinical practice was the topic of a recent Case-Based Rountable event moderated by Marcia S. Brose, MD, PhD, director of the Center for Rare Cancers and Personalized Therapy, and director of the Thyroid Cancer Therapeutics Program at Abramson Cancer Center of the University of Pennsylvania School of Medicine in Philadelphia, PA.

PROOTHI: We do genetic molecular testing and also genetic counseling on these patients. I don’t have any patients with MTC.

BROSE: You would do it up front as you would do for lung cancer, I take it?

PROOTHI: Yes, plus the genetic screening too.

BROSE: Are there any additional people who have had a patient with MTC? Is there additional screening that you would order?

BACH: I don’t see really any MTC cases. I would imagine we do next-generation sequencing [NGS] and get one of those huge panels and determine whether or not the RET mutation is on there. I’m not sure. I would definitely have to look into that. I think I usually do that based on whether there are treatment options available, and since we know that there are…that sometimes drives me to look for those particular mutations on that form of testing, whether that’s polymerase chain reaction, fluorescence in situ hybridization, or NGS, but I imagine NGS.

BROSE: It is NGS. It’s an interesting point. Would you order mutational testing?

MA: I’m starting with mutational testing first.

BROSE: More mutational testing. Right, because [if the] germline [testing information] hasn’t come back positive, we don’t know any information. If they didn’t have it, you definitely would want to get the somatic testing.

PROOTHI: [A patient like this] should have received [systemic therapy before he is] symptomatic [with short] doubling time.

BROSE: The problem about waiting until symptoms [appear] is even if [patients] have really great responses, sometimes the damage caused by the tumor, even if the tumor regresses, doesn’t necessarily resolve the symptoms. A classic one for a lot of my patients with thyroid cancer is when they end up with a pleural effusion. You can treat that tumor but then that effusion can really haunt them for a long time. I would have voted for treating this patient earlier on.

Papillary thyroid cancer has RET fusions 10% to 20% of the time, and this is a lot higher than I honestly ever thought I was going to see. But I already have treated 2 patients in my papillary group that I was screening and even I know there are a lot of BRAF mutations in papillary. I send off both the fusion panel and the point mutation panel for papillary [thyroid cancers] now because we are picking up both TRK and RET [alterations] at a pretty significant level.

[RET alterations in] MTC are very common, 60% to 90% [of the time].¹ [I’m not sure about] 90%, but certainly 60% in patients who have systemic disease.

BROSE: We have vandetanib [Caprelsa] and cabozantinib [(Cabometyx), which] are the initial FDA-approved agents, and [then] selpercatinib [Retevmo] and pralsetinib [(Gavreto) were also] both FDA approved. [We have phase 2 data for] sorafenib [Nexavar]. Can you please discuss your answers and why you picked what you did?

PROOTHI: I picked the selpercatinib only because I have some experience [with it] in lung cancer. Plus, we have the approved drug, and we have the point mutations.

BROSE: Dr Proothi, you were saying that you agree with starting earlier, and I agree with that. What would have been your trigger for you to initiate therapy?

PROOTHI: [If a patient is] symptomatic, there’s no point waiting. He should have started even before he became symptomatic. I don’t have the doubling time before that, but I know he had systemic disease, probably in his liver.

BROSE: I agree. I think if I saw progressing liver lesions, that would have probably been enough to get me to do it. I’m not sure about cabozantinib at this point [as] systemic therapy. It is an interesting choice because this is a pretty aggressive disease, but I think in the case of somebody [with a known] RET mutation [there are] some good data. I think I would probably pick selpercatinib first. But cabozantinib was an interesting alternative choice.

BROSE: [In the LIBRETTO-001 trial, in the patients with RET-mutant MTC who were previously treated], 9 of [55] had complete responses. This was amazing because we hadn’t seen any of this before with the other prior FDA-approved agents. In the not previously treated [patients] there were 11 complete responses.²

Durations of response were not reached in most cases because of the fact that they were so prolonged. Progression-free survival in the not previously treated [patients] was 23.6 months….I don’t think you can get a better curve than [the duration of response in the not previously treated group with MTC]—completely horizontal.

[Regarding] treatment-related adverse events [AEs], the grades 3 or 4 were much less than we would see in the vandetanib or cabozantinib arm. Primarily hypertension was the main one with LFT abnormalities and a handful of grade 4 [events], but really very few. Dose reduction [was in] only 30% of patients and discontinuation in only 2%, so really a very good safety profile.³

GOLDBERG: I think it’s very impressive. A great group of patients, brand new data, and a brand new drug that certainly is best in class, I think there’s no doubt about that. The off-target toxicities certainly are much better managed than [those of] cabozantinib. I think it’s excellent.

GOLDBERG: I have a question about the clinical trial: [Were] all those [patients enrolled on] progression, [or were] they all-comers? [For example], the cabozantinib [patients] who were all [treated on] progression and there was a difference compared with the vandetanib[-treated patients]. Maybe that’s an illustration [for] why [patients in the LIBRETTO trial] did so well?

BROSE: They had to have progressive disease on LIBRETTO.

GOLDBERG: Well, that makes it much more impressive.

BROSE: [That was the population looked at in the] cabozantinib [trial] after the [vandetanib] ZETA trial [NCT00410761]. All the other trials [since then] have had that as a standard.

MA: I think these data are really marking a new era in targeted therapy. We had other first-generation targeted therapies mostly in non–small cell [lung cancer], EGFR [mutant], and even ALK, with all these newer generation inhibitors hitting different diseases’ unmet needs.

BROSE: I would have been happy with efficacy data like these or the safety data like these, but then you get both of them and you [think], wow t blows my mind, I agree.

BACH: I was one of the people that [voted for] pralsetinib because I didn’t really know the data. LIBRETTO was pretty impressive in that respect. Because you never know when you have the mutation which one [to use]. I mean if they’re both approved and they’re both on National Comprehensive Cancer Network guidelines, which one might be the better [choice]? But I think that from the [LIBRETTO-001] data now I can understand why 70% of the people picked it.

BROSE: In the ARROW study [of pralsetinib], the overall response rate was 60% [in the previously treated patients] or 66% [in the tyrosine kinase inhibitor–naive group], with complete responses in 1.8% up to 10%. This is comparable, but maybe a little bit less than what was seen in the LIBRETTO study. Partial responses were [seen in] 58% and 55% [of patients], and the median duration of responses was not reached in either case. The follow-up was not that long, but the duration of response [rate for] over 6 months was at least 79% and 84%.⁴

If we look at the AEs in the patients, the main one was hypertension in the ARROW study. We had a little bit higher numbers and 40% of patients had grades 1 to 4, but 21% had grades 3 or 4 hypertension. That seemed to be a little bit of a difference as far as the 2 drugs go, otherwise [they were] fairly comparable as far as a very good toxicity profile.⁵

It has to do with lab values. There was a little bit more bone marrow suppression with pralsetinib compared with selpercatinib, and that probably has to do with the fact that it’s not quite as tight of a RET inhibitor. It has a little bit of RAF inhibition, and that probably affects the bone marrow a bit.

The FDA approved pralsetinib in December last year. We are using it, [and have had] a patient with tumor lysis syndrome. I sometimes wonder whether other patients might have had tumor lysis syndrome, but people didn’t sit down to calculate the 5 different things you have to have to qualify for tumor lysis syndrome. But regardless, I don’t really think that’s been a major problem with this drug. I guess if you have somebody with a rapidly growing tumor, no matter what, especially with these targeting agents, you have to really look for that.

MA: I don’t have experience using pralsetinib, particularly in this setting, but I’m curious about the AE profile question of whether one sees the same pneumonitis in the use of this agent in thyroid cancer [as in] non–small cell lung cancer.

BROSE: Interestingly, we didn’t, and I wonder whether some of those patients have had radiation and that’s adding to it or not. But we didn’t see idiopathic pneumonitis in the thyroid cancer group. Now, it just may be that there weren’t that many of them. It’s a small study, it’s not a large phase 3 trial. I think what’s interesting about all these kinase inhibitors [is that] every time the FDA approves them on a very small number of patients, what I notice is that they make us keep the study open for a very long time even after it has [been approved].

Right now, in both ARROW and LIBRETTO, patients are still being followed. I think we’re going to get more longterm follow-up because that’s one of the requirements of the FDA: We’ll give you FDA approval, but you’ve got to follow them longer. We’ll really have good 3-, 4-, and 5-year data on all these patients. It’ll be interesting to see.

GOLDBERG: Tumor lysis syndrome in solid tumors is an oxymoron. As a hematologist-oncologist, [I think] it’s bizarre. I wouldn’t be too worried about it. I think it’s just a fluke of a very rare subgroup of patients.

BROSE: It’s somebody who’s responding very well and it’s an outcome of that. We used to see it with chemotherapy in small cell lung cancers, but it really hasn’t been as big of a deal in these solid tumors.

_REFERENCES:

_{1. Subbiah V, Cote GJ. Advances in targeting RET-dependent cancers. Cancer Discov. 2020;10(4):498-505. doi:10.1158/2159-8290.CD-19-1116}

_{2. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. doi:10.1056/NEJMoa2005651}

_{3. Retevmo. Prescribing information. Lilly USA, LLC; 2020. Accessed May 27, 2021. https://bit.ly/3yHG0I6}

_{4. Subbiah V, Hu MIN, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors. J Clin Oncol. 2020;38 (suppl 15):109. doi:10.1200/JCO.2020.38.15_suppl.109}

_{5. Gavreto. Prescribing information. Blueprint Medicines Corporation; 2020. Accessed May 27, 2021. https://bit.ly/3kMI8b1}