TRK Inhibitors: A Tumor Agnostic Approach to Treatment of Solid Tumors - Episode 5

Safety and Efficacy Profile for TRKi-Larotrectinib

July 15, 2019

Marcia Brose, MD, PhD:As the population has expanded, were there any changes in the safety signals that you were seeing?

David Hong, MD:No, and that’s what’s kind of remarkable about this drug. This trial has been going on, especially the phase I, and I still have patients on that trial.

Marcia Brose, MD, PhD:As do I.

David Hong, MD:Yeah, seriously. The safety signal really has not changed. Occasionally—and this is not in all patients—patients who stay on the study longer do sometimes get a myalgia, muscle pain, when they do not take their drug on time. But overall, these adverse events are very mild. The dizziness is probably 1 of the more common adverse events, and it seems to improve over time. None of the liver toxicities seems to have gotten worse or been concerning as the trials continued.

Marcia Brose, MD, PhD:Then you bring up a good point because people are on these drugs for a really long time, which for many kinase inhibitors can be challenging.

David Hong, MD:Yeah.

Marcia Brose, MD, PhD:Can you tell us a little about the patient-reported outcomes that were presented?

David Hong, MD:Shivaani Kummar, MD, FACP—our colleague at Stanford University—presented the patient-reported outcomes for which they used the EORTC [European Organization for Research and Treatment of Cancer] QoC [quality of care] criteria, and showed significant increase in these patients’ quality of life essentially, starting before they started the trial and after. Almost 70% of these patients had significant quality-of-life improvement.

Marcia Brose, MD, PhD:How long did it take for them to start experiencing that? Did they say?

David Hong, MD:Offhand, I don’t know the answer to that, but at least in my experience, most of these patients will tell you within days to weeks they have.

Marcia Brose, MD, PhD:A data set as soon as after the second cycle.

David Hong, MD:Yeah.

Marcia Brose, MD, PhD:That’s amazing. What about the safety and efficacy profile of larotrectinib, which is obviously very good? Can you just talk a little bit about how it compares with other types of options? And that’s hard because we obviously have many tumor types.

David Hong, MD:Correct. In this refractory population—if you’re talking about other options, for example, sarcoma—for many of these patients who’d gone for the trial, there were no options. The options were standard chemotherapy. If you ever treat a patient withNTRKfusion with larotrectinib, you don’t forget it cause these responses are incredible and for many of these patients, the therapy is life changing.

Corey Langer, MD:As I mentioned, the response rates are quite high. The durability seems quite good. Toxicity is fairly tolerable. We do see some constipation and edema, some fluid retention, some episodes of paresthesia and mild neuropathy. Although for the most part, these [adverse] effects are grade 1 or grade 2. No showstoppers in terms of systemic toxicities, and that’s critically important for any agent that’s going to be given orally and continuously.

With chemotherapy we often contend with acute nausea, vomiting, transient neutropenia, but patients recover from that. You can’t tolerate those sorts of toxicities on a long-standing basis with oral agents that are given daily.

The updates have shown that many of these partial responses have now deepened into complete remissions. The CR [complete response] rate appears to be about 10% to 12%. We’re starting to see higher numbers of lung cancer patients in the original series: 3 of 4. Now I think they’re up to about 10 or 12 patients. It’s still a very small percentage overall who haveNTRKabnormalities with lung cancer, and actually it’s a relatively small percentage on the trial [who] have lung cancer. No major surprises. Essentially just a deepening and broadening of the original data that were cited in the landmarkNew England Journal of Medicinepaper.

Transcript edited for clarity.