Updates on Biomarker-Directed Therapy for Solid Tumors: Focus on NTRK, RET, and NRG-1 - Episode 12

Tumor Agnostic RET Inhibition: The ARROW Trial

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Dr Jyoti Patel presents data from the ARROW clinical trial.

Mark Socinski, MD: I’m going to ask Dr Patel to give us her thoughts about the subsequent RET inhibitor, pralsetinib, and walk us through the ARROW trial. Those populations were very similar to what we saw in the LIBRETTO-001 trial, which was very nicely summarized by Lori.

Jyoti Patel, MD, FASCO: It is a very similar. The pathway was perhaps the Blueprint Medicines Corp—the company. Thank you, Lori, for smiling. That took me a minute.

Lori Wirth, MD: That was good; I got it.

Jyoti Patel, MD, FASCO: Thank you for that. The ARROW trial was a registrational phase 1/2 study design in which MTC [medullary thyroid cancer] and non–small cell lung cancer were both well represented. It was any RET alteration. The lung cohort was reported first with the fusions, and similarly, patients could come on as treatment-naïve. Those patients had response rates that were 73%; the response rate of patients with prior platinum treatment was a little bit lower at 61%, but remarkably 100% of patients had some tumor shrinkage. The waterfall plot went across the board. Again, regardless of the fusion partner, we saw a long duration of response as well. Toxicity was mild, with about 20% of people experiencing hypertension or some transaminitis.

The updated data set for medullary thyroid cancer with RET aberrations was a little more recently presented. That included 53 patients. The response rate was 60%, with some complete responses. The median duration of response, again, was not reached. For patients who were treatment-naïve, their response rate was about 82%. Again, we are seeing this broad activity. Anecdotally, for patients with lung cancer who we treated with platinum prior to this—patients who had received some immunotherapy as part of their prior platinum treatments—I think had a little more toxicity with both of these TKIs [tyrosine kinase inhibitors]. Patients who received platinum alone seemed to tolerate treatment really well. I think we are seeing how that evolves as more patients are treated. Regarding CNS [central nervous system] responses, I had a couple of patients with leptomeningeal disease who had good responses. Both drugs are quite active.

Mark Socinski, MD: Obviously, the CNS data come from small patient numbers, but it is pretty active in the settings that we’ve seen. Ben, what is your sense of the selpercatinib versus pralsetinib comparison?

Benjamin Levy, MD: It may be another Coke versus Pepsi situation here. I have a lot more experience with selpercatinib than I do with pralsetinib. I think both of them—if you look at the waterfall plots of both of these drugs—look fairly similar, even though the response rates are a little higher in the selpercatinib data versus the pralsetinib data. Each of them has different toxicities with which we must wrestle. We were fortunate enough to participate in Lori’s trial with patients with thyroid cancer, and we also had patients in it with lung cancer. It was a very well-tolerated drug. Again, it is a win to have this embarrassment of riches compared to what we had before. I think both are extremely well tolerated and elicit meaningful responses below the neck and above the neck, intracranially. I believe only 2% of patients in the selpercatinib study had to come off therapy for any reason, and only 4% of those in the pralsetinib had to come off treatment. It speaks to the selective nature of these drugs and how well tolerated and how targeted they are.

Mark Socinski, MD: It is interesting; we talked a little about this at the very beginning, the role of molecular testing at the time of disease progression. I think there has been at least 1, if not more, small series presented about this topic…. It was patients with EGFR mutations and osimertinib developing RET fusions as their acquired resistance driver. There has actually been activity in that setting, which is interesting, and although it is quite rare, it would be part of the argument for retesting at the time of progression in other oncogenic driver subsets. I am not sure if it has been described in any other setting other than the EGFR mutation-positive population.

Jyoti Patel, MD, FASCO: We contributed to that experience, and it is an interesting progression when you have off-target progression. This is when you see more of the fusions with really potent inhibitors. I think, for drugs like selpercatinib, which will end up being great on target, there are hot spots where you will pick up some more off-target mutations. That’s certainly been noted with the NTRK experience as well. Some of these toxicities are overlapping though, QTc [corrected QT interval] prolongation and transaminitis, and so we need to be careful when we start mixing.

Mark Socinski, MD: I completely agree that we first consider safety. We have to be sure, particularly when treating some of our patients who may have other comorbidities. I think it is great to have 2 options. I mentioned before, regarding “The Pathways of Progress” that Ross Camidge MD, PhD, and I co-chair; we had this debate where we considered selpercatinib versus pralsetinib. You can probably guess that it was a Coke versus Pepsi thing. We could not distinguish based on toxicity. We could not distinguish based on efficacy. There is not enough experience with these drugs for us to confidently know any cost issues, but that may be the leading factor moving forward. We know that the pricing and cost of these expensive oncolytics in the oral setting can vary based on contracts and so forth. There are a lot of things to learn in that particular area.