RET Inhibition Research: Next Steps



Robert Doebele, MD, PhD: The task ahead of us is to start to understand resistance mechanisms to RET gene fusion. There have been a little data now published at meetings suggesting that solvent-front mutations are going to be seen. That leaves the door open for the development of new RET TKIs [tyrosine kinase inhibitors] that can overcome that type of resistance for this, so hopefully having later-line selected TKI options for patients who become resistant to pralsetinib or selpercatinib.

The other exciting space that we’re starting to see is, we’ve observed at least in a handful of cases that RET gene fusions are actually resistance mechanisms to other targeted therapies. We've seen RET gene fusions as resistance mechanisms to osimertinib in patients who are EGFR mutation positive, or patients with RET gene fusions who are resistant to alectinib, which is a tyrosine kinase inhibitor for an ALK.

And there's already been some published data on combining drugs to overcome this resistance. I think, again, that's made much more possible by having selective drugs without a broad toxicity profile from hitting other kinases, so having selective RET inhibitors also allows us to combine these drugs better to overcome resistance in other disease settings.

I think the data from these selective RET inhibitors is going to make a meaningful difference for this population of patients with RET gene fusions in the same way that it has made a significant difference for patients with lung cancer who have other oncogene targets in their cancers. And I think it further emphasizes the need for broad testing in all of our patients.

There's really no excuse now to be doing a Singleplex assay or sequential testing because there are so many potential targets for our patients and so many good drugs that we really want to be identify the appropriate therapy for our patients, whether they're RET gene fusion positive or other oncogene positive patients so that we're giving everyone the right therapy up front.

Jessica Bauman, MD: RET inhibitors will certainly add to the armamentarium of treatment options that we have for patients with non–small cell lung cancer. Although, yes, this is a rare population of people, it absolutely adds a significant treatment option for the people who have this tumor. And I think what is most significant and remarkable in lung cancer over the course of the last decades is how we have created this environment of precision oncology for our individual patients.

And although, yes, we used to treat everybody with the same treatment, we now can individualize treatment for the individual patient so that they have the best responses, the best survival, the best toxicity profile so they can live for as long as they can with the best quality of life they can in the setting of an advanced illness.

Shirish M. Gadgeel, MD, MBBS:I think that, first of all, it’s very exciting that we have new drugs that are going to be available for another group of patients with lung cancer in a relatively short period. This is very exciting for our patients. It does make it a little more complicated for us because there is another gene alteration that we need to be aware of and that we need to ensure that our patients’ tumors are being tested for this alteration, to be sure that an appropriate test has been done. As I mentioned, a DNA-based NGS [next-generation sequencing] assay may not identify all translocations. It is essential that we are aware of that information and that the laboratory that we are sending the tumors to does perform an RNA-based NGS assay.

Finally, it is also important to note that in RET translocations there can be multiple gene partners. With ALK, in over 80% of the patients, the gene partner is the ML4, whereas in RET there are multiple gene partners.

Now, with multikinase tyrosine kinase inhibitors, we found that the drugs may not be as efficacious with each of the gene partners in RET translocated non–small cell lung cancer.

Early data suggest that that differential efficacy is not seen, that is RET-specific inhibitors appear to be beneficial in all RET translocated non–small cell lung cancer, but these data need to be further analyzed and try to assess whether that remains to be true.

In addition, we are starting to see progression in patients treated with RET-specific inhibitors, and we’re starting to learn the mechanisms of resistance that lead to patients progressing on these drugs. And based on that understanding, there are now novel RET inhibitors that are coming into clinical trials.

And so one needs to now become familiar with these drugs, as well, so that patients who are treated with RET-specific tyrosine kinase inhibitors when they do progress, we make our patients aware of these trials with these novel drugs, which may end up providing them the most clinical benefit, in addition to the other treatment options that we already have.

Transcript Edited for Clarity

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