Repotrectinib Adds to the Treatment Armamentarium for NTRK+ Advanced Solid Tumors

The efficacy displayed by repotrectinib (Augtyro), including in patients who have received a prior TRK TKI, demonstrated its utility as a treatment option for select patients with advanced solid tumors harboring NTRK gene fusions, and it could improve quality of life (QOL) for these patients compared with palliative chemotherapy, according to Luis E. Raez, MD, FACP, FCCP, FASCO.

On June 13, 2024, the FDA granted accelerated approval to repotrectinib for the treatment of adult and pediatric patients 12 years of age and older with solid tumors harboring an NTRK gene fusion that are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and that have progressed after treatment or have no satisfactory alternative therapy.¹

The approval was supported by data from the phase 1/2 TRIDENT-1 trial (NCT03093116), which demonstrated that TRK TKI–naive patients with advanced solid tumors harboring NTRK fusions (n = 40) achieved an overall response rate (ORR) of 58% (95% CI, 41%-73%). The median duration of response in this population was not estimable (NE), and the 12-month DOR rate was 86%.²

In patients who previously received a TRK TKI (n = 48), the ORR was 50% (95% CI, 35%-65%), and the median DOR was 9.8 months (95% CI, 7.4-12.9). The 12-month DOR rate was 39%.

“The ORR data, particularly in TKI-naive patients, underscore the efficacy of repotrectinib and supports its approval for this indication,” Raez said in an interview with OncLive^®.

In the interview, Raez highlighted the implications of the FDA approval of repotrectinib, expanded on the data derived from TRIDENT-1, and detailed the safety profile of the TRK TKI. Raez is the medical director at Memorial Cancer Institute, oncology research director at Memorial Health Care System, director of the Thoracic Oncology Program at the Florida Society of Clinical Oncology, and clinical associate professor of medicine at Florida International University in Miami.

OncLive: What is the significance of the accelerated approval of repotrectinib for patients with advanced solid tumors harboring NTRK fusions?

Raez: [NTRK] genetic aberrations are called fusions because there is an exchange of DNA material between chromosomes. [Fusions] are important in cancer because they are not only present in one tumor; they are present in many different tumors [in both adult and pediatric patients]. That's why every time that we get [a pan-tumor approval] approved by the FDA or the European Medicines Agency, we are not getting approval for one cancer; we are getting an approval for multiple types of cancer.

The first drug [to receive pan-tumor approval for patients with solid tumors harboring NTRK gene fusions] was larotrectinib [Vitrakvi] in 2018. I was part of [one of the] studies [that supported the approval of larotrectinib], and data showed the agent was useful in at least 18 different tumors. That [approval] was historic because they were not approving a drug for [only] lung cancer or breast cancer. We call these tumor-agnostic approvals because these drugs work in several different cancers, as long as the cancer has the genetic aberration that we are targeting.

Patients [present] with [NTRK] genetic aberrations in many different tumor types. Previously, patients with NTRK fusions would only get palliative chemotherapy most of the time. These agents that we are developing for NTRK genetic aberrations are good. [TRK TKIs] are giving patients the opportunity to prolong survival significantly with a good quality of life compared with palliative chemotherapy, which can [be associated with] short survival and more adverse effects [AEs]. That's why these drugs are important.

What is the primary mechanism of action of reprotrectinib?

We have a family of genes called NTRK, and when these genes develop genetic aberrations—a fusion of these genes—patients develop cancer. [NTRK fusion–positive] cancers arise as many different tumors. We have been engineering drugs that target these specific genetic aberrations: NTRK1, NTRK2, or NTRK3. Reprotrectinib is joining [the treatment armamentarium] because we have good data showing that it works by targeting genetic damage caused by NTRK genetic aberrations.

What was the design of the TRIDENT-1 trial?

Like a lot [trials] for novel drugs now, we did not develop this trial for one distinct patient population. TRIDENT-1 had 7 cohorts of patients [including a phase 1 dose-escalation cohort and 6 phase 2 dose-expansion cohorts]. The first four cohorts [in dose expansion] observed patients with another genetic aberration called ROS1. Cohorts 5 and 6 included patients with NTRK genetic aberrations. One of these cohorts was for patients [who were naive to a TRK TKI], and the other cohort was for patients who had already been treated [with a TRK TKI]. The approval for reprotrectinib was based on these two cohorts of the trial.

TRIDENT-1 was only a phase 2 study, so we were assessing efficacy and some safety. There was no comparator arm and no randomization because these NTRK genetic aberrations are very uncommon. Finding patients with these genetic aberrations takes time. [For this reason, many] FDA approvals for patients with rare genetic aberrations are based on phase 2 studies like this one. We don't have to do the phase 3 trials comparing a new drug against placebo. That is what is required for other [drugs] in indications that are much more common.

What were the key efficacy findings in TRIDENT-1?

In the cohort of patients who were TRK TKI naïve, the ORR was 58%, and the 1-year DOR rate was 86%. We still don't know the median DOR because is hasn't been reached. We have to keep following the study to see when we are going to reach that number.

In the other cohort of patients who were pretreated [with a TRK TKI], the ORR was 50%. The 1-year DOR rate [in this cohort was 39%]. [These data show that] even in these patients who have already received treatment [with a TRK TKI], they still have a chance of response. [Many] times when we talk about TKIs, if you already give [a patient] one of these oral agents and then give a second one, the response is not as good [with subsequent TKIs] because the patient's tumors are already resistant and more aggressive than the original tumor during the treatment with the initial TKI.

Regarding the safety profile of repotrectinib, are there any patients in whom you would hesitate to use this agent?

No, because this agent is from a class of oral agents [where we already have approved drugs]. For [patients with solid tumors harboring] NTRK fusions, we already had two FDA-approved agents [larotractinib and entrectinib (Rozlytrek)]. Repotrectinib is now the third one. This agent shares an AE [profile] that we see with other [TRK TKIs]. For example, one of the most common AEs is dizziness. Patients [can also experience] change in the taste. Patients can have peripheral neuropathy in their hands and in the tips of their fingers. Other AEs are common with any other anti-cancer agent, such as constipation, dyspnea, and fatigue.

Some of the AEs [for repotrectinib and TRK inhibitors] are peculiar—most anti-cancer drugs do not cause dizziness, dysgeusia, or peripheral neuropathy—and sometimes doctors are a little bit uncomfortable because they are dealing with AEs that we are not used to. For example, all oncologists deal with leukopenia. This is something we deal with [almost] every day and are familiar with. Therefore, when [clinicians observe] AEs that are uncommon, some may be a little hesitant [about a particular drug]. However, the good thing is, we [have been] using this family of drugs for several years.

[Most doctors] in America or Europe may not be used to dealing with some of these AEs, but I don't think [they] will hesitate to use [repotrectinib] in this approved indication. For example, 65% of patients had dizziness, which can be annoying for the patient and may impair their QOL; however, [the rate of] severe dizziness that would impair QOL was less than 3%. In other words, [the majority of patients had] a little bit of dizziness, but [most did not have it] to the point that we have to discontinue the drug. Seven percent of the patients [from all study cohorts (n = 426)] had to discontinue the drug because of a treatment-emergent AE. That's why I think the AE profile is not going to be a problem for the use of this agent.

The other good thing about repotrectinib is that [for] oncologists in Europe and America, we already have experience with this drug [following its 2023 FDA approval for adult patients with locally advanced or metastatic, ROS1-positive non–small cell lung cancer (NSCLC)]. We have already had this drug approved for [patients with NSCLC harboring] ROS1 fusions, so we already have experience. We're already using it and are familiar with it. That's why I don't think there are any specific indications where I would not prescribe this drug; however, this should be evaluated patient by patient.

How will this approval impact clinical practice?

We need to see if this agent is better than the other two we have [that were previously approved] for patients with solid tumors harboring NTRK fusions. In the case of the other genetic aberration that repotrectinib is approved for—ROS1—we have found that the data that repotrectinib brings are much more appealing. For [patients with] ROS1 genetic aberrations, repotrectinib was the [most recent agent] to be approved, and it's probably the agent of choice today. We have enough information to say that it doesn't matter if it was approved later, it is the more effective agent compared with the others we have. We need more information [in the NTRK fusion space], but even if its [efficacy and safety] are the same as the other agents, it's going to benefit a lot of our patients.

As I mentioned, this indication is not for only one type of tumor. I only treat [patients with] lung cancer, but patients with salivary gland tumors or sarcomas, [for example], can also derive benefit. This is true whether patients are adults or kids, and that is why this is very exciting for our cancer community. [As more drugs like this are developed], we can provide our patients with better survival and QOL compared with palliative chemotherapy.

References

1. FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. FDA. June 13, 2024. Accessed June 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-repotrectinib-adult-and-pediatric-patients-ntrk-gene-fusion-positive
2. Solomon BJ, Drilon A, Lin JJ, et al. Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: update from the phase I/II TRIDENT-1 trial. Ann Oncol. 2023;34(suppl 2):S787-S788. doi:10.1016/j.annonc.2023.09.2405