TRK Inhibitors: Evolution of a Tumor-Agnostic Treatment Approach - Episode 3

Updated Data for Larotrectinib


David S. Hong, MD: The abstract that we presented at ASCO [the American Society of Clinical Oncology annual meeting] this year—there were actually a number of abstracts, but of the 3 abstracts I think were key, 1 was the abstract on the long-term follow-up on adults, with 83 patients, which is a significant number more than the 55 that included pediatrics in the 3 studies, phase I NAVIGATE II and the pediatric SCOUT study, in the original indication. The other abstract was Dr Shivaani Kummar’s study on patient reported outcomes. And lastly, Dr Alex Drilon had a really important oral presentation on the efficacy of larotrectinib in patients with CNS [central nervous system] metastases and primary CNS malignancies.

In our abstract of 83 adult patients, I think the 2 key points that came out of that was first that the overall response rate was equivalent to the initial approval of indication of approximately 75%, 76% for the investigator reviewed response rates. But also important was the duration of response, overall median progression-free survival, and overall survival. All these didn’t have enough data in the original application. The overall duration of response was not reached. We still had patients on for very long periods of time. The median progression-free survival was approximately 25.8 months, over 2 years, if you think about it. And the median overall survival has yet to be reached, which also suggests both the durability and the efficacy of larotrectinib in this patient population.

David Hyman, MD: Although the study really was not designed to look at the difference between upfront treatment with TRK inhibitors or patients who received this as a later line of therapy, there is a signal of a high response rate, a response rate of approximately 80%, across the study population, and it doesn’t seem to be carried by patients who were treatment-naїve. So we think that response to TRK inhibitors occurs regardless of prior therapy because that prior therapy is not interceding upon this oncogene addiction to TRK. So we really believe these inhibitors are effective across all lines of therapy.

David S. Hong, MD: Of our abstract in the adult population, what we reported both in ESMO [the European Society of Medical Oncology] last year, and the data that have now accumulated for many of these patients for long periods of time, the longest patient who has been on the study has been on for almost 5 years since phase I. And what we know from this is that this drug is incredibly well tolerated. The vast majority of adverse events or toxicities are things like fatigue, dizziness, and mild nausea. These were all mild, grades 1 and 2. There haven’t been any new adverse events that have emerged in these patients who stayed on for long periods. We do know that the drug can cause, in a small subset of patients, some hepatotoxicity. Oftentimes, it’s just an increase in both the liver functions, AST [aspartate aminotransferase] and ALT [alanine transaminase]. These are reversible. We just usually hold the drug or dose reduce larotrectinib, and usually this resolves. Patients do respond even at lower doses of larotrectinib under 100 mg twice daily.

Transcript Edited for Clarity