The Future of RET Inhibition in Clinical Practice



Jessica Bauman, MD: We are hopeful that the 2 RET inhibitors for which we have the most impressive data recently, BLU-667 and LOXO-292, will be FDA approved some time. We know that they've received FDA breakthrough designations. And so the hope is, with more data and longer follow-up, we'll see approvals for both of these drugs in the future. They have been tested, for the most part, in the second-line setting, with a little bit of data in the frontline setting.

So although right now we absolutely will consider these strongly for our patients, it is unclear as of now whether we should be treating these patients up front with RET inhibitors. However, what I will say is that we saw with patients with EGFR and ALK mutations, that those inhibitors very quickly moved to the front-line setting, and that's where we saw the best responses. And so, I anticipate that that is exactly what we're going to see with RET inhibitors as well.

Robert Doebele, MD, PhD: Once these selective RET inhibitors are FDA approved, I think we're going to see a rapid uptake of these drugs for patients. And these will likely, I think, be first-line choices for our patients. And really, that's based on the remarkable activity, relatively safe toxicity profile, and also years and years of data suggesting that these targeted agents are almost always superior to chemotherapy, when we see objective response rates above 60%, progression-free survival that's in the range of 1 to 2 years, and especially with intracranial activity.

These drugs really win on all fronts. The expectation is that these will become the new first-line therapy. And again, that will only occur if we're broadly testing our patients because, of course, we have to identify the right patients who have RET gene fusions to give them first-line therapy. It'll make that testing component even more critical. When we think about sequencing though, again, selective RET TKIs [tyrosine kinase inhibitors] will be our first-line therapy of choice. And that leaves what will we do after that.

Chemotherapy is an obvious choice. I think chemotherapy\immunotherapy also will remain a choice. We don't have a lot of data on patients who are RET gene fusion positive and received chemoimmunotherapy, although in general, chemoimmunotherapy seems to be superior to chemotherapy alone for patients with unselected non–small cell lung cancer. Again, we don't really have data in patients who are RET fusion positive.

I think one thing that we can say from multiple retrospective trials is that monotherapy immunotherapy [I/O] with things like pembrolizumab and nivolumab are not very effective in patients who are RET gene fusion positive. And that probably that should not be given as monotherapy, given 2 very nice retrospective studies, one by Oliver Gautschi, MD, and the other by Alex Drilon, MD, looking specifically at patients who were RET gene fusion positive and treated with immunotherapy and had very high disease progression rates and very low response rates, even in the setting of high PD-L1 [programmed death-ligand 1].

And so I think it's critical to remember that PD-L1 and some of these oncogene driven subsets do not behave the same way. It's not as good of a predictive marker for benefit from monotherapy, immunotherapy, or checkpoint inhibitors such as PD-1 [programmed cell death protein 1] and PD-L1 inhibitors.

Shirish M. Gadgeel, MD, MBBS:The data observed with LOXO-292 and BLU-667, the 2 RET-specific inhibitors in clinical trials, are quite impressive and very comparable to drugs that we use in patients with EGFR mutation-positive lung cancer, as well as drugs that we use in patients without translocation non–small cell lung cancer, in that the response rates are higher than 60%, with even higher response rates observed in patients who are treatment naïve.

The initial results regarding progression-free survival suggest that this could potentially exceed 16 to 18 months. These clinical efficacy results are extremely promising with these drugs, and I do believe that these drugs will end up being the standard of care for these patients as frontline therapy.

RET translocated non–small cell lung cancer has all the clinical features that suggest that frontline I/O therapy may not be as efficacious, in that RET-positive non–small cell lung cancer patients, generally, are never smokers, generally have adenocarcinoma, 2 features, and generally have tumors that have low tumor mutation burden.

Features that are very similar to patients whose tumors have EGFR mutations or ALK translocations, in a group of patients who had frontline single-agent I/O therapy, it has not been as efficacious.

And based on the data that we have in EGFR and ALK, I believe that once these RET-specific targeted agents are approved that they will be the preferred choice compared with I/O therapy. Now, when exactly they will be approved remains to be seen, but based on the available data and based on the fact that the FDA has given priority review to both agents, one hopes and anticipates that they will be approved in a relatively short time.

Trancript Edited for Clarity

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