TRK Inhibitors: A Tumor Agnostic Approach to Treatment of Solid Tumors - Episode 9

Entrectinib-Selective ROS Inhibition

July 15, 2019

Marcia Brose, MD, PhD:Were there different adverse effects observed with that agent compared with larotrectinib that you know of?

David Hong, MD:As I recall, there were definitely different adverse effects. I think less hepatotoxicity but other adverse effects such as diarrhea, etc., were observed that we didn’t necessarily see as frequently in larotrectinib. That’s probably from the inhibition ofALK-ROSas well.

Marcia Brose, MD, PhD:And as far as the safety signals other than just the adverse effects?

David Hong, MD:I think the safety signals are very similar to larotrectinib in the sense that overall entrectinib also is a very safe drug. The studies, I think, have been going on longer with entrectinib, in theNTRKpopulation, than the STARTRK studies show. But I think the overall safety signals are very similar. Both these drugs are not very toxic.

Marcia Brose, MD, PhD:I appreciate your comment that you really can’t compare because the trials are very different, and you really can’t compare directly across them. Hopefully as we get more data, we’ll actually be able to know a little bit more.

Does theROS-ALKinhibition from entrectinib affect the efficacy in lung cancer? We often see those mutations in lung cancer, but you’re not going to see bothTRKandROS.

David Hong, MD:Correct. It’s an effective drug inALK-ROSpatients, andROSspecifically. I think they’ve reported response rates up to 60% or higher.

Marcia Brose, MD, PhD:Is it more active inROS-mutated patients than inTRK, for instance?

David Hong, MD:The data would suggest it’s more effective inROSor at least the waterfall plots in response rates. I’ll be honest with you, I don’t know the answer to that.

Marcia Brose, MD, PhD:I think the data for theTRKalone is so few that it’s really going to be hard to say. I guess we’ll know again when the datasets get bigger.

Would you have a certain population for whom you might pick entrectinib over larotrectinib? Or are there certain patient populations, because of this data, for whom you would say that if they have CNS [central nervous system] mutation, you would pick 1 over the other?

David Hong, MD:Again, I’m biased. If you have anNTRKfusion, I would go on larotrectinib. If you have aROS, orALK-ROS, that’s debatable, because there are a lot of other drugs right now. There are other drugs right now in this class that are incredibly effective that you’d have to ask the lung experts to figure out where does that fall in which space.

Marcia Brose, MD, PhD:We have to split off that activity and study it completely separately.

Corey Langer, MD:In terms of how I expect to use this class of agents, my experience to date is exactly 1 patient who has enrolled on a clinical trial of entrectinib and actually did, in fact, have a response. I’m sharing that patient with another colleague, so I’m not primarily taking care of this individual. The presumption is—if we identify this marker at the get-go as part of next-generation sequencing and their initial work-up—more likely than not we will treat this individual with the targeted agent. We’ll defer other forms of systemic therapy. That’s not true of all molecular abnormalities. For instance,C-Metmutations or amplifications preferentially use chemotherapy first or chemotherapy combined with PD-1 [programmed cell death protein 1] or PD-L1 [programmed death-ligand 1] inhibitors. But in this case, if anNTRKrearrangement has been identified, these individuals will get larotrectinib and presumably, once it’s approved, entrectinib. At that point we’ll start asking the question, “Can we sequence these agents? What’s the activity of 1 after the other?” Currently those are essentially unknown.

Ultimately, though, one expects that these individuals will become TKI [tyrosine kinase inhibitor] refractory. In that group, chemotherapy necessarily remains the final common pathway—whether to give chemotherapy with angiogenesis inhibitors like bevacizumab, whether to continue the TKI along with the chemotherapy. Again, a number of open unanswered questions exist.

Transcript edited for clarity.