Evolution of Precision Medicine in Non–Small Cell Lung Cancer - Episode 13

RET-Fusions in NSCLC: Updates From ASCO

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An overview of the RET-fusion data updates that were presented at the American Society of Clinical Oncology (ASCO) 2021 annual meeting in non–small cell lung cancer (NSCLC).

Benjamin Levy, MD:We’re going to move on now to the bona fide gene fusions. We’ve had some updates from ASCO [American Society of Clinical Oncology meeting]. We’ll start with RET fusions. We’ve had approvals for selpercatinib and pralsetinib recently. Jacob, may you give us high level the data that we have now and how potentially to use these drugs? And there were some updates at ASCO but just at a very high level these 2 drugs’ traction within RET fusion space.

Jacob Sands, MD: We can talk about them similarly. Pralsetinib and selpercatinib both approved drugs, and the audience is familiar with these given their approvals. But it is a rare fusion, it’s something to make sure that people are truly looking for because if they’re missing out on something, RET fusions might be one to make sure that they’re looking at. What we’ve seen with this is essentially very good response rates. Selpercatinib, the data that was presented looked at both those who were treatment naїve as well as those who were second line therapy. The waterfall plots are what we see across a lot of different targeted therapy treatments with very high response rates, particularly in those who were treatment naїve. We saw overall survival at 2 years of 88% which is just astonishing in the treatment-naїve setting and such different numbers than the lung cancer numbers that were discussed 10 years ago around the time that IPASS had been published.

It was well tolerated. Not much in the way of grade 3 toxicities. I’ll say from participating in the phase 1 study of selpercatinib, we saw responses even down at the 20-mg initial dose and pretty well tolerated even at higher doses than what’s currently the standard of care. On top of that, we also see good CNS [central nervous system] responses, and that was presented by Dr Drilon [Alexander Drilon, MD] as well. It is a smaller number of patients but increasing with a nice percentage of responses and good CNS disease control. Also, then Dr Subbiah [Vivek Subbiah, MD] presented on pralsetinib. I can say we see comparable numbers. Overall, we’re seeing nice responses to therapy, durable responses, CNS disease control, well tolerated. It’s really, It is for RET but osimertinib has been for EGFR in a lot of ways. There’s a lot of comparable results there and a clear advance.

And then RET goes back to your prior statement just to highlight. People need to look back, make sure that their patients were tested for these things. If they were tested, if someone got a NGS [next generation sequencing] panel 2 years, did you notice that there’s a RET fusion because we have this therapy? And if not, the first patient I put on this was early in the phase 1 trial, someone who I’d recently put on hospice who then I found out we had this phase 1 trial that was going to open soon, and she had a RET fusion. And I called her and brought her back into clinic and she had 2 years of disease control, living by herself, doing well. But the only reason that was found is because I had gotten an NGS panel on her at the time of her initial diagnosis. And I suspect there are multiple other patients out there that can benefit from this. We just have to notice them.

Benjamin Levy, MD: Yes, I agree. We were fortunate enough also to participate in the clinical trial of selpercatinib, a clean drug with meaningful activity, both in lung cancer and thyroid cancer. You mentioned testing, Jacob and what are the optimal ways to test for RET. There’s a lot of confusion out there. Is it FISH [fluorescence in situ hybridization]? Is it DNA-based NGS? Is it DNA with RNA NGS? How’s the optimal way, what is the optimal way to detect these fusions?

Jacob Sands, MD: Yes, I mean some of this is going to differ by institutions. And within our institution, we have an internal DNA panel that they’re pretty confident with fusions in that as well. But fusions are a little different than mutations and so that’s something you need to follow up with, your assay and how that’s being tested. FISH is a way of looking at fusions, and so that’s certainly something that a lot of pathology departments are familiar with is doing FISH assays. RNA is something that is more institution specific. There was data out of Memorial Sloan Kettering that was impressive as far as catching some of these various genomic alterations by looking at RNA testing in those who were negative by DNA testing, but that is something that seems institution specific as far as whether or not doing RNA testing. It depends upon that baseline assay that’s being used.

Benjamin Levy, MD: Melissa, I’ll ask you the unfair question I asked Alex. Between pralsetinib and selpercatinib, any meaningful differences at all? Do you use one over the other?

Melissa Johnson, MD:I’ll give a similar answer. These are similar drugs in terms of potency in CNS activity. We also participated in the selpercatinib phase 1 trial, and that does tend to be what I write for first. But next door at Dr Spiegel writes for pralsetinib first. It is a plug I suppose that the sooner that you let us use your drug, even in the community, the more likely we are to prescribe it long term.

Benjamin Levy, MD: I would agree. I have a lot of familiarity from the trial with selpercatinib. I’m a creature of habit and it’s what I’m familiar with, but both are meaningful in their activity. If you look at the waterfall plots, they look similar.