Targeting TRK Family Proteins in Patients With Solid Tumors

Alexander Drilon, MD

The more research reveals about the presence of NTRK gene fusions in various solid tumors and the activity of the available TRK inhibitors, there is potential for better precision medicine in the community setting. Most recently, data presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting show the promise of larotrectinib (Vitrakvi).

Across multiple studies, larotrectinib elicited robust and durable responses in both adult and pediatric patients, including patients with central nervous system (CNS) involvement.

Among 244 adult and pediatric patients treated, the overall response rate (ORR) was 69% (95% CI, 63-75), which included complete responses (CRs) in 26%, and pathological CRs in 5%. Partial responses (PRs) were achieved in 43% of patients, stable disease (SD) in 17%, and progressive disease (PD) in 8%. Response in the remaining 6% were not determined.

Another analysis of 93 evaluable pediatric patients with NTRK fusion-positive cancer showed that larotrectinib achieved an ORR of 84% (95% CI, 75-91). Response consisted of CRs in 38%, which included 2 pending confirmation and pathological CR in 46%. There was also 2 pending PRs, SD in 12% of patients, and PD in 2% with the remaining 2% not determined.

In the CNS tumor population, larotrectinib achieved a high disease control rate and manageable toxicity. The ORR was 30% (95% CI, 16%-47%), which included CRs in 8% of patients, PR in 22%, SD for 24 weeks or more in 43%, SD for less than 24 weeks in 14%, and PD in 14%. The DCR of 24 weeks or more was observed in 73% of patients (95% CI, 56%-86%).

As a first step towards treating a patient with an NTRK fusion-positive tumor, the fusion must be identified. Also, considering the rarity of these fusions and limited exposure to this patient population in community practice, knowledge of how to test for NTRK fusions is important, according to Alexander Drilon, MD.

“In terms of testing, we now know that there are active agents like larotrectinib, and entrectinib (Rozlytrek) for the treatment of NTRK fusion-positive cancers. So, testing to find these fusions is important. With this tumor agnostic approval, there are many ways to do this. In an ideal setting, we found that the optimal way to find these fusions is to do comprehensive next-generation sequencing of not only DNA, but also RNA,” Drilon, a medical oncologist and chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center told Targeted Oncology™, in an interview.

Drilon discussed NTRK gene fusions in solid tumors, collective findings of studies assessing larotrectinib for the treatment of these fusions, and how to conduct genomic testing to identify patients who might benefit from TRK inhibitor therapy.

TARGETED ONCOLOGY: What does the science tell us about the post-developmental physiologic processes associated with TRK proteins?

Drilon: The TRK family of proteins is intimately involved in both the development and maintenance of the nervous system. From a practical perspective, in adults, that means that it controls things like appetite, the functioning of nerves that are involved in maintaining balance, and other nerves. When they are irritated or hyper activated, that might result in paresthesia.

Can you talk about  NTRK  fusions and how they manifest differently in older vs younger patients?

NTRK fusions are found across many different cancers both in adults and in pediatric patients, and that includes infants, children, adolescents, and young adults. The different cancers that are found in adults vs the pediatric population include a higher frequency of some rare tumors in kids or infants like congenital fibrosarcoma, for example. While there are othermore common cancers where the frequency of an entrapped fusion is lower, such as lung cancer, gastrointestinal tumors, or non-secretory breast cancers, where those cancers cluster largely in the adult population. There is a difference in the profile of the tumor types that we see in infants and kids, adolescents, vs adults.

Can you discuss the available TRK inhibitors for the treatment of lung cancer?

There are 2 approved TRK inhibitors for the treatment of any cancer with an NTRKfusion, and 1of them is called larotrectinib. It is a selective inhibitor of TRK A, B and C. The second one is called entrectinib, and that is a good inhibitor of TRK A, B and C but it's a multi kinase inhibitor that also hits for ROS1 and has to a lesser degree activity against ALK.

Both of these drugs are approved in a tumor agnostic fashion and beige agnostic fashion for patients whose cancers harbor these fusions. Approval has been granted in many different regulatory environments around the world. Now, there are next-generation TRK inhibitors that are currently in clinical trials. Examples are selitrectinib [formerly LOXO 195], repotrectinib [TPX-0005], and taletrectinib [AB-106]. These drugs are designed to target resistance mutations that might emerge with the first-generation agents.

At ASCO this year, you are presented updated findings on larotrectinib. Can you discuss the methods of your analysis?

This year, we saw a regulatory update to the activity and safety of larotrectinib. As a reminder, this was in a program that looked at 3 different clinical trials. This was a basket trial program with an adult phase 1 and a pediatric phase 1 and 2 trial called SCOUT [NCT02637687] and NAVIGATE [NCT02576431], which is an adult and adolescent phase 2 basket trial.

In the update presented at ASCO there were now 244 patients with non-primary CNS and NTRK fusion-positive cancers that received larotrectinib. The baseline characteristics were aligned with what we've seen with prior data sets. Again, this was a data set that included a pediatric and adult population, so the age ranged from infants of point 1 year to 84-year-oldadults. The most common cancers or soft tissues sarcoma, infantile fibrosarcoma, thyroid cancer, salivary lung, and colon cancer,as well as a few new cancers like duodenal and urothelial tumors made their way into the dataset.

Thankfully, the overall data in terms of activity was comparable with prior data sets. In this update, the objective response rate was 69%. The complete response rate was 26% with a pathologic complete response rate of 5%, and a partial response rate of 43%. We're certainly seeing a very active drug, with a majority of patients having benefited with the therapy regardless of tumor type. Many of these patients stayed on for a very long time. Some of them were pushing 5 years.

If you look at the waterfall plots, with a median duration of treatment that ranged from up to 60 from 0.1, up to 67.9 months now the median duration of response, progression-free survival [PFS], and overall survival [OS] were 32.9 months with a 28.3-month follow-up,29.4 months for PFS with a 29.3-month follow-up, and not reached for median OS with a 32.2-month follow-up.

Safety wise, the data set was also expanded to 269 patients, but there were no new or unexpected safety signals. This was a report that showed what we've seen in prior reports with the most common treatment emergent or related [adverse events] being mainly grade 1 or 2. The typical rare neurologic side effects such as dizziness, for example, or imbalance were noted, but not at a dramatically different frequency. In conclusion, we have much more data that the drug has been explored in more patients, more cancer types, and continues to work just as well, which is good news for patients and providers alike.

What does new research show about the safety and efficacy of larotrectinib in lung cancer?

At ASCO this year, we also saw an update to the lung cancer-specific activity and safety data of larotrectinib. A total of 26 patients with NTRK fusion-positive lung cancers were treated on that same program with a primary objective of response. The baseline characteristics were not different from that previously reported. It included everyone that had valuable target lesions had disease progression or therapy.

If you look at the swimmer plot, the objective response rate was 83% and 80%. In patients with CNS metastases, many patients had either a partial or complete response to therapy. Interestingly, no patients had primary progressive disease. In terms of treatment duration, the longest ongoing case was 52.7 months, and the median duration of response, median progression-free survival, and the median overall survival had not been reached for larotrectinib, which is highly encouraging.

The safety also was not different from a prior report of the adverse effects of larotrectinib. This essentially was not different either from the update of the tumor agnostic data set that I just spoke about. This is an approved drug for patients with lung cancer in a tumor agnostic context. Of course, it continues to show great efficacy and is very tolerable lending itself to long term dosing in patients who are matched to this treatment.

What do these collective findings tell us about testing for  NTRK  gene fusions? What testing advice can you give for community oncologists.

In terms of testing, we now know that there are active agents like larotrectinib, and entrectinib for the treatment of NTRK fusion-positive cancers. Testing to find these fusions is important. With this tumor agnostic approval, there are many ways to do this. In an ideal setting, we found that the optimalway to find these fusions is to do comprehensive next-generation sequencing of not only DNA, but also RNA. The latter maximizes the chance of finding these fusions becauseintrons are very expensive, or there are other factors that lead to a lower likelihood of only finding the fusions on DNA in our center.

We've had a good experience with doing both to increase the number of fusions that we find. However, there are different practice environments. If you look at the guidelines that are out there, there are other tests that could be employed. That includes FISH, for example, but you need to do 3 different ones for the 3 different genes immunohistochemistry, which looks for expression as a surrogate for the presence of a fusion but doesn't actually find the fusion. But tests like those can be used to screen for these NTRK fusions, if you're in a practice environment where you may not have insurance, or payer coverage for a more comprehensive testing.

In general, my advice is that people might look at this and say that I've never seen a patient with an NTRK fusion, or in the cancers that I treat, the frequency is rare. But as you can see from the data that's been presented, not just the activity data, but also the safety data, that we have really good drugs. Finding one of these fusions is essentially a jackpot for someone because things can turn around substantially. They can be on it for a very long time, much longer than some of our standard treatments like chemotherapy.

I think that as a community, we need to come together to try to increase things like coverage for molecular profiling awareness so that we know to test for this. Hopefully, by doing that, we'll get ourselves to a better place where it's not so onerous to try to find these, orwe do a large comprehensive test, as mentioned, that looks for this and several other drivers of oncogenesis that might match your patient with a targeted therapy.