Response to Larotrectinib Carries on With Long-Term Follow-Up of TRK Fusion+ Cancers

Marcia S. Brose, MD, PhD

With longer follow-up, treatment with larotrectinib (Vitrakvi) maintained robust and durable tumor-agnostic efficacy, as well as survival prolongation in adult patients with TRK fusion cancers. The benefit was observed even in those with central nervous system metastases, according to an analysis of 3 clinical trials of larotrectinib.

Larotrectinib is a first-in-class, highly selective, TRK inhibitor, and considering the prevalence of NTRK gene fusions in various cancers, and the activity of larotrectinib in the central nervous system (CNS), investigators started exploring its outcomes. Since then, larotrectinib has become an FDA-approved therapy for adult and pediatric patients with TRK fusion-positive cancer.

The analysis looked at 140 adult patients with 20 difference tumor types of which 130 were evaluable for efficacy. The objective response rate (ORR) observed with larotrectinib was 67% (95% CI, 58–75), which including complete responses in 12% of patients, partial responses in 55%, and stable disease in 20%. Nine percent of patients had progressive disease.

Safety results showed grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 12% of the populations. There was also 1 patient who discontinued larotrectinib due to a TRAE. No new safety signals were observed.

In an interview with Targeted Oncology™, Marcia S. Brose, MD, PhD, Emeritus Professor CE of Otorhinolaryngology, Head and Neck Surgery in Department, at the Perelman School of Medicine at the University of Pennsylvania, discussed a multiple trial analysis of patients treated with larotrectinib over a median of 24 months.

TARGETED ONCOLOGY™: Can you about the development of TRK inhibitors and solid tumors? In which diseases are showing the most promising right now?

BROSE: TRK inhibitors were originally developed as a pain treatment because it affected cells that express TRK, which are usually in the central nervous system. Subsequently, it was realized that TRK fusions are present in several solid tumors, and because of that, it led to the first trials for larotrectinib. In patients with solid tumors, any solid tumor that had a TRK fusion, I think that the largest number of these when we did the clinical trial were in thyroid cancer, a type of salivary cancer, lung cancer much to a lesser degree, but you know, it's pretty common to have, even if it's only 1%. In lung cancer, there were still a significant number of TRK fusions when you think about the total number overall. And the biggest one is soft tissue sarcomas, which were mostly seen in children.

So, the idea was that these TRK inhibitors might be useful for patients who have any sort of TRK fusion, and I have to say they are multiple other cancers I didn't even mention, where occasionally you'll find a TRK fusion. So, the idea was to do something that targeted what was considered the cause of the tumor, and so oncogene addiction, this was really felt to be likely the causal, genetic alteration that led to the tumor development. By inhibiting the TRK pathway, it was hoped that this would work. So, it led initially to a phase 1 study. There was a phase 1 and then phase 2, followed by phase 1/2 trial in pediatric cancers, where patients were then put on larotrectinib.

The dose that was determined from the phase 1 was 100 milligrams twice daily. And the original FDA approval was based on the first 55 patients that were enrolled across those 3 studies. It was such remarkable data. Patients with widespread metastatic disease, with no hope got such a good response. There was a good response rate and prolonged responses, and that it why the FDA approved it early. So, the poster that I presented at ESMO is really a follow up of that data going forward.

What were the key goal of your pooled analysis?

What this trial did was it took all of the patients that have been enrolled the process through trial. So initially, as I said, there were the 55 patients. Now there have actually been over 140 patients treated across those 3 trials. And the idea was to look at the data further out at a later cutoff time to see if the early data held up. We also looked at safety to see whether or not there might be any additional safety signals. And of course, we also, with a little bit more time, wanted to know what was the progression, median progression-free survival, median duration of response and median overall survival, to find out how those work. So, the primary end point had already been raised, the effective response rate had already been assessed. We'll look at that as well. But we also wanted to flesh out a little bit more of these secondary end points.

Can you discuss the efficacy findings from this analysis? Were the any differences observed between the first 55 patients and the 140+ patients?

The most important thing we saw was overall response rate. When we look across all adult patients, the median, the overall response rate was 67%. When we look at all the adult patients who had CNS metastases at baseline, their overall response rate was actually 73%. I'll point out that wasn't the actual lesions in the head, but mostly patients who had metastatic disease in their head. We saw that in 15%. When we take all comers achieved a complete response, another 72% of patients achieved a partial response, and another 26% achieved stable disease as their best result. So, there were significantly robust responses, and that was the primary end point.

When we looked at the secondary end points such as median duration of response, we were really encouraged because the median duration response at this point was now 49.3 months. This is quite remarkable over 4 years as a median duration of those patients who had responded, if we look at the median progression-free survival, it was 25.8 months. So, patients can really expect regardless of their tumor types to have a progression-free period of25.8 months on average, or even longer, if they are a responder. As I mentioned, we look at the median overall survival, and it still had not been reached. I think that's particularly informative, because patients in this situation, many of them had widely metastatic disease. So, these results are telling us that patients who do respond to this therapy are going to do well, they're deep responses, and they seem to be durable.

For oncologists who are using their larotrectinib in practice right now, what should they take home from this presentation?

I think the point they should take away from this presentation is to test before they start therapy because these were attractive and well tolerated to some degree. If an oncologist is possible to get a patient on 1 of these and in a prolonged response, I think we really owe it to the patients to do that before we start pulling out more toxic treatments that have less likelihood of actually producing significant durable responses. So, testing early is number 1, Number 2, if they are TRK-fusion positive, we have to understand the data related to TRK fusion treatments, which are attractive in their tumor type, because I think that that's going to be a breakthrough for a lot of these patients.

_REFERENCE:

_{Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase (TRK) fusion cancer. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 535P.}