Dr Piotrowska outlines the RET tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib, which are available for patients with RET fusion-positive mNSCLC, then Dr Neal follows with a discussion of supporting efficacy data from the LIBRETTO-001 and ARROW trials.
Joel Neal, MD, PhD: So Zosia, we found a RET alteration and this patient is untreated. What are the drugs that you'd think about using here?
Zosia Piotrowska, MD: So, we're fortunate to have two selective RET tyrosine kinase inhibitors I think to choose from in this case, pralsetinib and selpercatinib, and I think one of those two agents would be my preferred first line therapy for a patient with a RET fusion identified in molecular testing. They're both drugs, of course we'll go through the data, but they're both drugs that are fairly well tolerated. They both have CNS efficacy. And I think they're both great treatment options for a patient like this. So certainly, I would choose one of the selective RET inhibitors for this patient.
Joel Neal, MD, PhD: Yes, the one that came out was selpercatinib, and these were data from the LIBRETTO-001 study. Again, the demographics showed a lot of patients that were never smokers, and I think of the RET alteration gene rearrangement similar to ALK and ROS and EGFR in those patients who tend to have a light or never smoking history. The efficacy outcomes, response rates were reasonably high with a response rate of 64%, duration of response in the 17.5-month range, and progression-free survival also high, 16.5 months, suggesting even patients without an objective response had a long duration until they had to switch to next line therapy. The change of tumor size was relatively independent of whether patients had had chemotherapy before or previous anti-PD1 or-. PD-L1 immunotherapy without a lot of off-target effects of increased side effects necessarily of prior immunotherapy leading in to TKI. And then I think by treatment status, both untreated patients and previously treated patients had good responses overall, showing that it looks like it's a perfect first line treatment option.
The ARROW trail showed, so as opposed to selpercatinib, pralsetinib at a dose of 400 mg daily. This very large trial with hundreds of patients, many of which were treated similar baseline characteristics, overall response rate almost identical, 61%. Disease control rate, 91%. And duration of response not even reached at the time of initial report here, it was so long. Most patients had changes regardless of RET fusion partner. As you said, Michelle, RET rearranges with a lot of different things, so fortunately we don't care about what the fusion partner is necessarily. Although maybe if a patient doesn't respond, then we'll have to refer for additional testing and try to figure out what's really going on. I'm always perplexed when the targeted therapy should work. We don't set expectations about finding a target and we do set expectations about the targeted therapy working, but every once in a while, it just doesn't work, and we don't really understand why.