RET Inhibitor Trial Updates at ASCO and ESMO

Transcript: Marcia Brose, MD, PhD: At the ASCO [American Society of Clinical Oncology] 2019 Annual Meeting, we had an update of the ARROW study, the BLU-667 agent in medullary thyroid cancer predominantly. That, again, showed extremely good response rate, with a total response rate, overall response rate, of 49%. What we did see also in the toxicity is a little more toxicity than we had seen in the LOXO-292 trial with a little more—I think it was about 14% grade 3 hypertension and 7% of patients who actually had neutropenia. And this is probably because of a little less specificity for RET and a little bit of additional targeting by the BLU-667. But still, overall, this is an amazingly well-tolerated agent. And like LOXO-292, if available, this would also be something I would consider in the first-line therapy.

Alexander Drilon, MD: BLU-667, or pralsetinib, is a selective RET inhibitor designed to avoid the off-target toxicities of older multikinase agents. It’s been tested in an ongoing program looking at RET-dependent cancers, including RET-fusion-positive lung and thyroid cancers and RET-mutant medullary thyroid cancers.

The drug has shown impressive response rates with an objective response rate in RET-fusion-positive lung cancers of 57%, and an objective response rate in medullary thyroid cancers of 47%. Fewer papillary thyroid cancer patients have been treated, so we don’t have large numbers to speak of just yet. With this early data set, the medians have not been reached.

In terms of toxicity, pralsetinib, or BLU-667, was also very well tolerated, with most adverse events related to drug being grade 1 or 2. There are some adverse events to watch out for that are seen with selective RET inhibition in general, including hypertension and liver function test abnormalities. And with this drug we’re also seeing some myelosuppression in select cases. But overall I think the program has really shown us that we have another active selective RET inhibitor that’s also well tolerated by patients with a variety of RET-dependent cancers.

Jacob Sands, MD: The comparison of these 2 drugs really is the current question. We see 2 very effective therapies, highly selective with a very good efficacy profile and adverse-effect profile that really outperform the multikinase inhibitors, which really makes the multikinase inhibitors no longer a part of the discussion, in my mind, and I fully expect both of these drugs to end up getting approval and likely standard of care in the frontline setting. As far as which ones to use, that’s the question we’re at now, I guess. And there are still a lot of data to collect. We do see good efficacy and manageable adverse-effect profiles in both cases. We still also have more data to collect from these.

As far as being able to say in a pinpoint reliable way what the actual, for example, CNS [central nervous system] efficacy is, we see signs from both with clear responses to therapy, but getting greater numbers of those is something that’s ongoing. The adverse-effect profile for both will continue to be collected, and we’ll see if there are any real changes. I don’t expect that. I expect them both to be pretty manageable. On the LOXO-0292 trial, we really saw very few people come off for any kind of adverse effects. With BLU-667, we see a bit more, but again still a manageable toxicity profile. And so as these studies are further developed and we get more information, that will kind of drive this discussion more. But I fully expect both drugs to end up being a part of the armamentarium and likely really utilized in the frontline setting.

Alexander Drilon, MD: Both selpercatinib and pralsetinib are designed to be selective RET inhibitors. Meaning they hit RET potently and try avoiding other kinases. I don’t think there are major structural differences between the 2 agents, and at the end of the day, we’re going to need to see much more longitudinal data, especially for pralsetinib, where the data set is a little smaller compared with selpercatinib. If we look ahead into the future, I’d like to see what their response rates look like in the larger number of patients, what the progression-free survival duration of response looked like, and also a comparison of adverse-event profiles between these 2 drugs.

Transcript Edited for Clarity