TRK Inhibitors: A Tumor Agnostic Targeted Therapy - Episode 7

Patient Selection and Responses to Larotrectinib

January 28, 2019

Shubham Pant, MD:Tell me a little bit about how this was another unique study that used patients with poor performance status. As we know, in solid tumors, for most of the clinical trials, patients need to have some particular performance status 01, they had to be fairly functional, able to be active with daily living, get around the house, go shopping, things like that. But in this trial, you included a number of patients who were doing much more poorly than that.

David S. Hong, MD:Yes. So I think that the FDA recognized, at least from the initial phase I data, the incredible activity that this drug in patients who hadNTRKfusion, and allowed for a little bit more relaxed criteria in the context of enrolling patients both in the phase II trial and I think also the pediatric study, given the unmet need. We did not put a whole lot of patients with the ECOG [Eastern Cooperative Oncology Group performance score] 3 on this trial to be frank.

Shubham Pant, MD:Can you explain to me, what is ECOG 3?

David S. Hong, MD:ECOG 3 just means based upon the performance status functionality, the criteria that patients who are probably bed-bound more than 50% of the day.

Shubham Pant, MD:So not very functional at all.

David S. Hong, MD:Not very functional.

Shubham Pant, MD:Can probably get around the house, do a few things, but mostly sort of spend time in a bed or a chair or a couch or something.

David S. Hong, MD:Correct.

Shubham Pant, MD:But I’ll tell you, on the weekends I do that, too, 50% of the time.

David S. Hong, MD:We did enroll a handful of these patients who had ECOG 3 who we identified withNTRKfusion. And one patient I remember who was fairly debilitated was in the hospital actually for pain, severe pain management, and was on oxygen. We were able to get her enrolled on a trial, even though she was in ECOG 3, and started her on larotrectinib, Vitrakvi, and she literally walked out of the hospital, off..oxygen, and pain free within a week after starting the drug, and still is on study almost a year and a half later as a hairdresser. And that’s a unique case. But you know what’s really fascinating about this drug, and I think, perhaps, TRK inhibitors, in general, are just the dramatic response that we’ve seen with these patients who receive it.

The first patient who actually received this drug was a young mom of 3 with sarcoma who had failed all known standard chemotherapy and had significant lung metastases and was on oxygen and went on larotrectinib and within the first restaging had a near complete response, and still remains on study almost over 3 years later.

And that is also I think what’s very interesting about this drug, or perhaps class of drugs—I would argue more so larotrectinib—but it seems like these patients really have a durable response for a fair long period of time, more so than other kinase inhibitors or small-molecule inhibitors in general. And that may just be the biology of these tumors, or, it’s not entirely clear but it may be, it may just be the biology of the tumors, but these patients do seem to have very good responses that are very durable.

Shubham Pant, MD:Tell me how, how fast have you seen responses? You just talked about it, but in general, when you look at the patients and everything does it take? Is it at first restaging, is about 2 months for most of this trial?

David S. Hong, MD:Yes.

Shubham Pant, MD:But how fast? When do you start to say, “OK, this is probably not working, or this is working.” What’s the average when you’ve look at all the patients.

David S. Hong, MD:So the average is usually around 2 months when that first restaging comes. The vast majority of patients who have are going to respond, usually respond in that first restaging. But we have also seen others. Interestingly, I had one mass tumor that did not have a partial response but eventually developed into an almost near complete response 8 months out. And so some of these patients can continue to respond over months, but it’s more common to see this dramatic response after the first restaging of these patients.

Shubham Pant, MD:And clinically do you see a response earlier? Do you see it in weeks?

David S. Hong, MD:Yes.

Shubham Pant, MD:Or does it take like a month? Clinically, you’re saying those patients of yours got off oxygen and everything.

David S. Hong, MD:Yes.

Shubham Pant, MD:On average, how often have you seen this?

David S. Hong, MD:Most of the clinical responses, whether it’s pain or whether it’s other symptoms, are usually fairly dramatically. But there are other tumors, as I shared with you, the mass tumors that may not have a lot of associated clinical symptoms. They don’t really notice anything other than maybe some shrinkage in their lymph nodes or so forth, but it can take a little bit longer for these patients to respond.

But, and I mentioned this to some of my colleagues, if you’ve ever treated a patient withNTRKfusion with either larotrectinib or entrectinib, or any of the TRK inhibitors, you want to screen everybody because of dramatic responses that you see in people.

Shubham Pant, MD:In solid tumors that you’ve not seen before.

David S. Hong, MD:Yes, especially in this chemorefractory population.

Shubham Pant, MD:I don’t mean to date you, but after having done this for more than a decade, right?

David S. Hong, MD:Yes.

Transcript edited for clarity.