TRK Inhibitors: A Tumor Agnostic Targeted Therapy - Episode 4

Analyzing Response Rates With Larotrectinib

Shubham Pant, MD:We’ve talked about a larotrectinib, and I know you are involved in the study for larotrectinib. Can you tell us a little bit about it? I know it was unique in a way that it was in pediatrics and in adults, and I was looking at the data that show that patients were from 0.3 years of age, which is a few months, all the way to even in the 70s.

David S. Hong, MD:Right, correct.

Shubham Pant, MD:So can you tell me a little bit about the study and what were some of the findings of the study.

David S. Hong, MD:Sure. So the data were presented in theNew England Journal of Medicinepaper—the data were presented by my colleague Dr Dave Hymen at ASCO [the American Society of Clinical Oncology Annual Meeting]—and most recently we presented the data at ESMO [the European Society for Medical Oncology Congress], which were additional data from those published in theNew England Journal of Medicine. Really it comprised 3 trials: the phase I trial, which I was involved in; the phase II NAVIGATE adult study, which I was also involved in; and lastly the SCOUT study, which was a pediatric study. And then they accumulated all the patients who hadNTRKfusions, looking at overall response rates, duration of response, etc.

The most recent data were presented at ESMO this past year, and there were about 122 patients in that data set. And what’s remarkable is that even from the phase I to this 122-patient data set, the response rates have remained relatively consistent. And that’s close to 85% of these patients. Or I’d say 83% of these patients have had some kind of partial response. And what’s even more remarkable, 17% of these patients have had a complete response. And as you know, Dr Pant, you rarely see this in solid tumors. And so that’s really exciting to see these data.

Shubham Pant, MD:So what we’re seeing is these are solid tumors in which patients who were put on the study had a complete response—that means that they couldn’t find tumor when the scans were done—or a partial response. I think there was significant shrinkage of the tumor, more than 30% by RECIST criteria.

David S. Hong, MD:Yes.

Shubham Pant, MD:So you were saying both in the pediatric and in the adult population, it was kind of similar; around 83% got a response.

David S. Hong, MD:Right. So if you look at the pediatric data, or SCOUT data, that response rate is probably even higher, almost close to about 90% partial response and also fairly high complete response. So it is a pretty dramatic waterfall graph, and I’ve rarely seen a waterfall graph like that in any study.

Shubham Pant, MD:That means you really saw a lot of responses. There were not so many who progressed. You saw mostly responsive patients. What did you find in patients who progressed? Was there something specific in those patients who progressed?

David S. Hong, MD:Yes.

Shubham Pant, MD:I’m not saying the ones who responded then progressed but the ones who just did not respond off the bat.

David S. Hong, MD:Yes. So there was a very small number of patients who did not respond. We don’t have the full data set. At least one of those patients in the data set had a pre-existing solvent front mutation, which put them at resistance to larotrectinib itself.

Shubham Pant, MD:Tell me a little bit about this mutation. It was a solvent front mutation?

David S. Hong, MD:Yes. It’s called a solvent front mutation, which is a change in one of the actual immuno acids that forms that ATP [adenosine triphosphate] pocket: solvent front or gatekeeper. These are just different names for different types of mutations that arise. And similar to other mutations that arise, whether it’s anEGFRor aKITmutation, etc, these mutations oftentimes cause a conformational change in that pocket so the drug cannot actually bind to that ATP, and so it no longer functions as a really viable drug.

Shubham Pant, MD:So it’s a resistance that you’ve seen where sometimes their resistance is such that the target is not there; it’s just not binding.

David S. Hong, MD:Right. It cannot allow the drug to conformationally bind to that ATP.

Transcript edited for clarity.