Landmark Approval in Tissue-Agnostic Targeted Therapy

Transcript:

Alexander Drilon, MD: The approval of larotrectinib is a landmark approval by a regulatory agency because it essentially represents the first targeted therapy approval for a specific gene signature that doesn’t take into account the type of cancer that a patient has. So long story short, if you have a patient with any particular cancer that harbors a track fusion—so these fusions are similar to ALK and ROS1 structurally, for example—then that patient would quality for a script for larotrectinib, which is given at 100 mg twice a day.

It’s also a landmark approval in a different respect. Specifically, this approval by the FDA covers not only adults but also children, knowing that a lot of these cancers that harbor track fusions are found in the pediatric population in select cancers like congenital fibrosarcoma, for example, or secretory breast carcinomas.

So this is a very exciting approval, obviously, and I think it marks a shift in the regulatory mindset, because prior to this, we already saw the approval of pembrolizumab for MSI [microsatellite instability]—high cancers of any type. And now after the approval of that immunotherapeutic, we have the first targeted therapy that’s approved agnostic of cancer type.

The regulatory, or the approval, dataset for larotrectinib was a pooled dataset from 3 different clinical trials. There was an adult phase I trial. There was a pediatric phase I trial, and then there was an adult and an adolescent phase II [trial], or basket study. And the primary dataset was a dataset of 55 patients who [were] consecutively screened for cancers that harbored a track fusion, again across adults and pediatric patients. And these patients obviously had cancers where the track fusion was detected by a molecular test. But on this trial, the doctors were allowed to do a molecular test that was local. Meaning that they didn’t have to send a central molecular testing assay for profiling, they could do any next-generation sequencing assay, for example, in their backyard to detect these fusions that thereafter allowed these patients to become candidates for the study.

I think that’s very important because it reflects the fact that if we use a good comprehensive test that’s readily available in your environment, for example, there’s a good likelihood that if you find a fusion that these patients stand to benefit from therapy.

The results from this combined dataset were really stunning. Again, we’re looking at any track fusion—positive cancer. So the efficacy results reflect the activity of the drug across many different tumor types. And the objective response rate was in the updated dataset; this was 104 patients. The objective response rate was 81%. And that’s high for any systemic therapy, considering, if you look across immunotherapy, chemotherapy, and even some targeted therapies.

And that reflects the fact that these cancers, even though they were of different types, as long as they had the track fusion, that they had a comparable proclivity for response to larotrectinib. And if you dive deeper into the dataset, we’ll note that the complete response rate was about 20%, so that was 1 out of every 5 patients. And, again, that’s a very high bar for a targeted therapeutic, really underscoring the fact that these tumors can be exquisitely sensitive to targeted therapy with the selective TRK inhibitor.

There were no differences in response based on the type of cancer that patients had. This, again, reflects the fact that we’re seeing that the most important piece in relation to response in patients [who] have a track fusion in their cancer, it’s really the presence of that gene signature, a track fusion.

Now I think that the longer we have follow-up on these patients, we’ll get a better sense of a difference, or a lack thereof, in terms of durability across different cancer types, of progression free survival or duration of response. But at least in terms of response in the up-front dataset, there doesn’t seem to be a strong tendency for one type of tumor to have a higher likelihood of response over another, but we’ll see what happens with much more mature data.

As we’ve seen with other targeted therapies, whether or not patients got a prior systemic therapeutic before receiving larotrectinib—meaning if they had gotten something like conventional chemotherapy or even immunotherapy prior to receiving targeted therapy—that didn’t seem to affect their likelihood of response. Again showing us that these tumors remain uniquely dependent on the track fusion for signaling and growth, and that’s not substantially affected by exposure to prior therapy. So there was no substantial difference in treatment-naïve patients versus those [who] had prior treatment.

Transcript Edited for Clarity