Expert Highlights Promising Findings With Larotrectinib in TRK+ Thyroid Cancers

October 25, 2018
Danielle Ternyila

Marcia S. Brose, MD, PhD,&nbsp;discussed the clinical benefit of larotrectinib in treating patients with&nbsp;<em>TRK</em> fusion&ndash;positive papillary thyroid cancer.

Marcia S. Brose, MD, PhD

The remarkably high response rates and low toxicity profile seen with larotrectinib in patients with TRK fusion—positive cancers make it the optimal choice for treatment, said Marcia S. Brose, MD, PhD.

“Once we have the translocation and they need systemic therapy, larotrectinib is what I’m looking to as a first- or second-line therapy since it is so well tolerated,” she said.

Larotrectinib is a highly selective TRK inhibitor that has shown promise for both adult and pediatric patients with TRK-positive cancers. In a combined analysis of 3 trials — a phase I study with adult patients, a phase I/II trial for pediatric patients, and a phase II study for adolescents and adults – the agent demonstrated an objective response rate (ORR) of 75% (95% CI, 61%-85%) by independent review and 80% (95% CI, 67%-90%) by investigator assessment in 55 evaluable patients. In pediatric patients with TRK fusion–positive solid tumors specifically, larotrectinib induced an ORR of 93%.

The trials included patients across 17 tumor types: salivary gland tumor (n = 12), other soft-tissue sarcoma (n = 11), infantile fibrosarcoma (n = 7), thyroid tumor (n = 5), colon cancer (n = 4), lung cancer (n = 4), melanoma (n = 4), GIST (n = 3), cholangiocarcinoma (n = 2), appendix tumor (n = 1), breast cancer (n = 1), and pancreatic cancer (n = 1).

In an interview withTargeted Oncology, Brose, associate professor of Otorhinolaryngology: Head and Neck Surgery at the Hospital of the University of Pennsylvania, specifically discussed the clinical benefit of larotrectinib in treating patients with TRK fusion—positive papillary thyroid cancer.

TARGETED ONCOLOGY:How frequently do TRK fusions occur?

Brose:There are 3 different TRK genes, they are numbered 1, 2, and 3 and they basically encode for 3 proteins. They are coded for what are called neurotrophin receptors. That gene is part of the kinase pathway, and it can be translocated with multiple partners that can cause abnormal signaling through the pathway.

In papillary thyroid cancer, we don’t really have good data that says exactly how much proportionally they are. We think they are somewhere between 5% and 25%. They are certainly not rare. It’s not super common, but they are present. There are specific therapies that target them in thyroid cancer.

In some types of head and neck cancers, they’re typically much higher, up to 75% of some of the patients, and given the different types of diagnosis, it can be very common in certain head and neck cancers. In squamous head and neck cancer, it’s probably a little bit more rare, more like 1%.

TARGETED ONCOLOGY:Could you share some of the findings we have seen with larotrectinib?

Brose:Larotrectinib has been studied now in 3 different trials. There’s an adult phase I, there was also a pediatric trial, and a phase II trial for basically treating any patient who had a larotrectinib translocation-associated tumor. These patients have been enrolled and about 55 of them were presented in the data at the original cutoff. Basically, the drug has been very active where virtually all the patients are getting a partial response or better. The response rate has been really quite high, and it really seems like it’s more targeted to these patients particularly.

If you look across, there are a couple of patients who didn’t get 30% or greater, but the vast majority of patients, regardless of the site of their translocation or tumor, have gotten responses of 30% or greater. It is exceedingly active, and unusually so, in how active it is.

TARGETED ONCOLOGY:What kind of adverse events (AEs) have been seen with this agent?

Brose:Overall, the AEs for this agent are extremely low, which is one of the other reasons we like it so much. Overall, most patients do not need to have dose reductions, and they all tolerate it very well. When you look at the whole set of 55 patients, there is only 1 AE that exceeds 10%, which is anemia. A lot of this could be due in part to the prior therapies that patients endured that affected their bone marrow.

It is extremely well tolerated, with the vast majority [of AEs] being only grade 1 or grade 2. The ones that I think personally are an issue sometimes are a little bit of dizziness, but that’s it. It was very well tolerated, at most it’s grade 1 AEs, which are all minor. They may be reported, but overall it did not affect the overall quality of life by any means.

When you look at the data from the grade 3 and 4, it is really almost non-existent in this drug, which is really unusual for a chemotherapy agent.

TARGETED ONCOLOGY:What would you say is the takeaway message from this data?

Brose:I think the takeaway message right now is that if you have a patient with a TRK fusion solid tumor, you want to get them on larotrectinib. There is no question that it is extremely well tolerated and it has a very high efficacy rate, which gives it a very large therapeutic margin.

TARGETED ONCOLOGY:Are there any next steps planned?

Brose:I think we want to continue to follow how patients are doing. With more awareness that we have this incredibly active agent, the next steps are to get as many patients tested as possible in the right context. I know that this data has changed my practice, in that I am now testing all of my papillary thyroid cancer patients at the time that they fail radioactive iodine. With that, we have already found 2 patients with the translocation. Now we really need to find these patients, that’s the next step. It has been practice changing from that perspective.

Once we have the translocation and they need systemic therapy, larotrectinib is what I’m looking to as a first- or second-line since it is so well tolerated.

TARGETED ONCOLOGY: Is there anything else you would like to add?

Brose:The amazing thing about this drug is there are patients out there who have widely metastatic disease or disease to the point where we honestly expect to end their lives, and within 2 to 3 months of starting this agent, they are now 3 years out. It’s pretty impactful to have an agent that works that well. This is a really unusual situation that does not happen often.

If you look at the data, I’m not alone. There are multiple complete responses. I’m not the only one, a lot of us are having this experiences which are pretty remarkable.