Early Development of TRK Inhibitor-Larotrectinib


Marcia Brose, MD, PhD:Why don’t you tell us a little bit about your work in the early development of larotrectinib.

David Hong, MD:I was involved in the phase I and phase II NAVIGATE study. In the phase I trial, the primary objective is to understand the underlying toxicities. At that time, it was not clear whether this drug would only work in NTRK [neurotrophic receptor tyrosine kinase] fusion patients. There were suggestions that it could work in other tumor types without necessarily NTRK fusions, but we quickly realized that the patients [whom] the drug benefited and affected were patients with NTRK fusions.

I remember seeing the scans of the first responder, who still remains on the trial almost 5 years later. She was a patient from Seattle, Washington, I think with Robert Doebele, MD, PhD, at the University of Colorado, who had this remarkable response. She was an undifferentiated-sarcoma patient who had been failed by at least 3 lines of chemotherapy, and in her lung scans, all her tumors disappeared in the first restaging.

In most phase I studies, you’re concerned about toxicity. Several years later and from results borne from larger data sets, we have learned that the drug is incredibly safe. There are toxicities of some dizziness, fatigue, and some mild nausea, but overall these are grade 1 to 2 events at most. There is a small percentage of the population who end up with liver AST [aspartate aminotransferase] and ALT [alanine aminotransferase] elevations. Oftentimes these are reversible. We hold the drug and even dose reduce, and the patients recover and do well. We’ve had some clear benefit with this drug, even at lower dosages than what is prescribed, 100 mg twice a day.

Marcia Brose, MD, PhD:I know that the AST and ALT elevations we see with these inhibitors are sort of transient ones.

David Hong, MD:Yeah.

Marcia Brose, MD, PhD:Can you talk a little bit more about the trial design. What were the inclusion criteria, and how are the populations included in the overall analysis?

David Hong, MD:There were 3 trials: the phase I trial; the NAVIGATE phase II, which was called the Basket trial—that meant anybody who had an NTRK fusion and different subsets of tumor types were allowed to enter the Basket—and a SCOUT pediatric study that explored different formulations, but particularly this drug, in a pediatric population.

The trials and those 3 data sets were included in the final NDA [new drug application]—breakthrough application, sorry—for the approval of larotrectinib. And the approval of larotrectinib was really a mini first. It was a first approval of a drug in both pediatrics and adults at the same time. It was not only the very first histology-agnostic approval but also the first genetic mutation or driver approval for any histology-agnostic indication.

Marcia Brose, MD, PhD:For those populations, we were talking about people who had already tested positive for a TRK fusion elsewhere, I assume, as the eligibility criteria? In the original studies, you were saying that everybody was invited initially. Did that change when you’re talking about studies with children of different ages?

David Hong, MD:Phase I was a typical phase I, in the sense that it was an all-comer solid-tumor study. As we reached the expansion, and as we reached in the phase II NAVIGATE study, it was restricted to only NTRK fusion patients.

Corey Langer, MD:Larotrectinib is 1 of the first examples of a tyrosine kinase inhibitor, a small molecule that’s undergone accelerated approval, really based on marker-specific activity. Responses are seen across a broad swath of malignancies—that all harbor a common molecular aberration, in this case NTRK.

This marker-specific approval is tumor- and histology-agnostic, and that’s what makes this approval quite unique. Because these markers, these rearrangements, are rare, we’ll never see a randomized phase II or phase III trial that’ll compare it with standard treatment. The numbers are just too small. Based on response rates now that are up 75% across the board, based on protracted progression-free survival that goingto exceed a year and a half overall, and based on the median survival that we haven’t even reached yet, I think it’s safe to say—at least in the realm of lung cancer and other refractory malignancies—that this agent will easily surpass chemotherapy de jure, another empiric systemic approach that is equally or at least unproven to date. In my mind, this sort of approval is completely ethical and actually absolutely necessary.

Transcript edited for clarity.

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