TRK Inhibitors in Lung and GI Cancers - Episode 10

Efficacy of TRK Inhibitors

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John L. Marshall, MD: Luis, let me shift to you a second and drill down more about the tumor types. You mentioned them earlier, but let’s go through them again. Were there certain tumors that were more prevalent? Were there certain tumor types where there was more benefit seen?

Luis E. Raez, MD: Yes. In 2018, when Alexander Drilon published in the New England Journal of Medicine—Mark just mentioned the paper—there were only 55 patients and 17 tumors. At that time, I remember, I was lucky to be part of that publication. We didn’t have a specific list of the response rate of the tumor, but it probably didn’t matter because there were very few tumors. But now that David Hong has published in The Lancet Oncology this year, we have expanded the number of patients. Now we have 155 patients, so we can at least start to see what the response is for certain tumors. For example, these are tumors that are very enriched with NTRK fusions like fibrous sarcomas.

I’d never seen a fibrous sarcoma—these are tumors in kids. For soft-tissue sarcomas, thyroid cancers, we have responses that average out to 80% to 100%. What is interesting to me in our business is that the responses for lung cancer and breast cancer are a little lower, maybe 75%, but also the number of patients are very old. There are only 10 to 15 patients with lung and breast cancer, and for pancreatic cancer it’s the lowest response, around 43%. But there are only 2 or 3 patients. I’m not sure we are ready to say the real response based on tumor type. It probably doesn’t matter because we are very lucky that the average response is high among the tumors.

But with time, as more patients are accruing and we have more of this information, we are going to be certain of what is the real chance of response for all these tumors.

John L. Marshall, MD: Yeah. I always think these tumors that are messy or that have multiple drivers respond less than the ones that are more driven by, perhaps, 1 gene. Shub, why don’t you take us through quickly? I want to go through a few studies with everybody, including the pooled analysis that was published in The Lancet Oncology and what it showed.

Shubham Pant, MD: Great. That’s what Luis was talking about. This is 1 of my colleagues, David Hong. We enrolled a number of patients on the trial as a group. Essentially the pooled analysis was for the phase 1 trial, which was an adult population. Then there was a phase 1/2, which was a pediatric population. And a phase 2 trial, which was an adolescent and adult trial. There were 3 trials that were pooled together, as Luis said—about 156 patients.

The interesting thing was that criteria, if you really look at it as you’re pooling, was 1 month or older. The cutoff was 1 month, so you had to be greater than 1 month old for enrollment on the pediatric trial. These patients had received some type of standard therapy that was previously available, so they were treated as if it was previously available. The response rate was 79%, the CR [complete response] rate was about 16%, and 63% of patients had a partial response.

Interestingly, as we said, the median duration of response was about 35.2 months, so that’s almost 3 years, and the progression-free survival was about 28 months. The amazing thing was the median overall for these tumors, which were advanced, was about 44 months. It’s amazing—that’s almost 4 years for these patients.

As I said, I’ve treated a number of these patients, and it’s very gratifying when they get the response. First, it improves their performance status. Quality of life is improved, and obviously their improvement of overall survival. They are very interesting pooled data.

John L. Marshall, MD: Yeah. Jyoti, Dr Patel, please give us a little review of what’s going on in brain metastases. Do these drugs work in that setting?

Jyoti D. Patel, MD: Sure. In the larotrectinib trials, a smaller number of patients were enrolled. If we look across the gamut, I think most patients who were enrolled were those with CNS [central nervous system] primary tumors. There were a minority of other cancers, such as lung cancer, which have a proclivity for the CNS metastases. But in those patients, 14 patients total, the response rate was good. It was about 55% and varied a little between histologic type.

This is 1 of the situations where CNS response is a little more difficult to quantitate. It’s probably similar to pancreatic cancer response, for example, where we don’t see those really robust response rates primarily because of prior treatment there or lesions that can be target lesions but had received prior treatment. So it’s a multitude of factors.

In this trial, what we see is that patients do respond. But more important, there was freedom from CNS progression and long duration of response. You’re preventing other disease, and this is really where you see the benefit. Certainly larotrectinib has an active CNS profile.

John L. Marshall, MD: That’s great.

Transcript edited for clarity.