TRK Inhibitors: A Tumor Agnostic Approach to Treatment of Solid Tumors - Episode 4

Efficacy of TRKi-Larotrectinib Among Tumor Types

July 15, 2019

Marcia Brose, MD, PhD:Tell us a little bit about the efficacy and the results that you saw in those studies.

David Hong, MD:Larotrectinib particularly has been the most effective small-molecule kinase inhibitor I’ve ever seen, and I’ve done a lot of clinical phase I trials. The approval data showed a 75% response rate. Of that, about a 20% complete response rate in metastatic solid tumor—which you know, Marcia, you and I have never seen before in any class of drugs. The data we presented, both in the adults, I think showed that this response rate continues even after we’ve enrolled; in the adult population it was an additional 83 patients. At this ASCO [American Society of Clinical Oncology Annual Meeting], when we presented it with the pediatric, it was like 105.

Since then we have enrolled even more. And what we’ve seen is that this durability of response is maintained. The actual duration of response has not been reached, which is incredible. The median progression-free survival in the adult data set in the abstract that we presented today was over 2 years: 25.6 months. That’s incredible. You know, I rarely see that with any small-molecule inhibitors, let alone any drugs. The overall survival has not been reached, so clearly I have patients on at least larotrectinib for years. The original patient—that phase I patient who initially was identified in the phase I—still remains on the study almost 5 years later.

Marcia Brose, MD, PhD:It’s great. I’ve met your patient, as it turns out. And what’s amazing to me about her story is the fact that her lungs were over 50% replaced by tumor. So when you’re talking about complete responses in these patients, it really is nothing short of remarkable. Can you talk a little bit about any differences that were observed between tumor types then? And she obviously had a sarcoma, I believe.

David Hong, MD:Yeah, a sarcoma. If you look at the label, there were some responses—some tumor types—that had lower response rate. For example, colorectal had a lower response rate, but the numbers were small. I think in the 55 patient days there were 4 patients. It’s not clear right now what the exact numbers are across all histologies. But if you took the overall population, it seems as if almost everybody who has an NTRK [neurotrophic receptor tyrosine kinase] fusion has some kind of response.

Marcia Brose, MD, PhD:Were there differences then also between patients who had been previously treated on chemotherapy versus people who were getting it in first line?

David Hong, MD:Not that we know of. Most patients who have significant chemotherapy-refractory disease tend to not be responsive to targeted therapies or new therapies. It did not seem to make a difference.

Corey Langer, MD:Responses with larotrectinib appear to be independent of tumor type. In fact, they seem to be pretty consistent across the board regardless of tumor type. Responses were observed regardless of the number of prior regimens that were administered to the patients, and that is a common theme in the world of personalized therapy or precision medicine, where we are using very specific agents against very specific targets. Prior history to some extent may influence outcome, but not to the extent that we’ve traditionally seen with systemic cytotoxics.

Recently, Alex Drilon, MD, who has been 1 of the key figures in the development of NTRK inhibitors, updated the non—small cell component of the larotrectinib story. There are only 4 patients with non–small cell in the originalNew England Journal of Medicinepaper. That’s now expanded to 11. Again, relatively small numbers, but the response rates are holding up in 7 individuals with measurable tumor. Four had partial responses to stable disease, and 1 had questionable disease progression.

No major surprises with respect to toxicity. We still see some fatigue and constipation, some edema, some fluid retention. The responses were quite durable. About 70% or so, and this is not just responses but stable disease—70% of those enrolled are maintaining freedom from progression at least a year. It’s nice to have a bit more data, considering the originalNew England Journalpaper included all of 4 patients. I suspect that as time goes on, we’ll see a lot more data that will further enrich our understanding of larotrectinib’s role, at least in non—small cell.

At this year’s ASCO, David Hong, MD, and colleagues updated the results of the original larotrectinib study, specially focusing on adults with a variety of malignancies, including salivary gland tumors, lung cancer, GBM [glioblastoma], thyroid carcinoma. The response rates continue to hold up in the 70%, 75% range. Again, no major surprises. When it comes to toxicities, we’re still seeing some constipation and edema and fatigue, but nothing that’s tough to manage or difficult to manage. Median follow-up of course is a bit more mature, roughly a year and a half. Median durations of response have not been reached yet.

Speaking of drugs, that activity level appears to be on par with the activity of alectinib and brigatinib and ALK-positive disease. And that is probably equal or surpassing that seen with even more modern EGFR inhibitors and third-generation agents like osimertinib. This is very exciting.

Transcript edited for clarity.