Full FDA Approval Underscores the Role of Larotrectinib in NTRK Fusion+ Solid Tumors

David S. Hong, MD

Although solid tumors harboring NTRK gene fusions remain rare, testing patients for these alterations is critical to identify patients who may be eligible for targeted therapies such as larotrectinib (Vitrakvi), according to David S. Hong, MD.

“With next-generation sequencing [NGS] being widely available to patients in the community and to community physicians, it’s absolutely worth testing your patients. If you identify a patient with an NTRK fusion, it’s like a lottery ticket for those with metastatic disease,” Hong explained in an interview with OncLive®.

On April 10, 2025, the FDA granted full approval to larotrectinib for the treatment of patients with solid tumors harboring an NTRK gene fusion without a known acquired resistance mutation; are either metastatic or where surgical resection is likely to result in severe morbidity; and have no satisfactory alternative treatment options or have experienced disease progression following prior therapy.¹

Pooled findings from 3 single-arm studies—the phase 1 LOXO-TRK-14001 trial (NCT02122913), the phase 1/2 SCOUT trial (NCT02637687), and the phase 2 NAVIGATE trial (NCT02576431)—supported the full approval of larotrectinib after the agent received accelerated approval in the same indication in November 2018.2

Across the three studies, evaluable patients achieved an overall response rate (ORR) of 60% (95% CI, 55%-65%), including a complete response (CR) rate of 24% and a partial response (PR) rate of 36%.1 Pathological CRs were observed in 5% of patients. The median duration of response (DOR) was 43.3 months (95% CI, 32.5-not evaluable).

In the interview, Hong detailed the implications of the full FDA approval of larotrectinib; his experience administering the agent to patients; and the importance of testing patients for alterations such as NTRK fusions.

Hong is the deputy chair of the Department of Investigational Cancer Therapeutics in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What is the significance of the FDA approval of larotrectinib for patients with NTRK fusion–positive solid tumors?

Hong: In November 2018, larotrectinib was one of the first tumor-agnostic targeted therapies approved [with its accelerated approval]. This full tumor-agnostic approval reaffirms what we understood in 2018. These patients [harboring NTRK fusions] clearly benefit from larotrectinib, regardless of tumor type/ There's always a concern with [accelerated approvals] that they can be rescinded, and then patients may no longer have access.

What guidance would you offer clinicians regarding the adverse effect (AE) profile of larotrectinib?

The profile of the agent is incredibly safe. There are some AEs, primarily dizziness, that patients may experience. AEs are usually easily managed by dose reducing the drug. There are some instances of elevated liver function tests, which are also relatively easy to manage by holding and dose reducing .

Overall, I’ve done a lot of drug development in my career in a lot of studies. [Larotrectinib] is one of the safest targeted agents I’ve [experienced]. It’s incredibly safe and well tolerated.

I’ve had patients [receiving larotrectinib as part of] a trial for close to 10 years, which is amazing. Some of them were the first patients enrolled in the [initial] phase 1 trial, and they are still on the study, doing great, and tolerating the medication even 10 years out.

I suspect that larotrectinib will be a well-tolerated drug [in clinical practice]. From the most recent data we just analyzed, which will be presented at the 2025 ASCO Annual Meeting, the median overall survival for patients [treated across the 3 studies]—excluding patients with central nervous system metastases—is [approximately] 44 months. That’s amazing. These are all [patients with] metastatic [disease] who were mostly chemotherapy refractory. To see that level of benefit in adult patients with NTRK fusions is an incredible outcome.

What guidance would you offer clinicians regarding the use of NGS when identifying patients who may be eligible for larotrectinib?

[I tell] patients and physicians that some community oncologists may only see 1 or 2 of these patients [with a tumor harboring an NTRK fusion] in their careers because they are relatively rare.

We currently don’t have cures. I’m not saying this drug is necessarily a cure, and many patients with metastatic disease will not be cured. However, if you’re able to identify these patients [with NTRK fusions] and get them on larotrectinib, it will undoubtedly extend their life.

My first recommendation to community doctors and patients is to get tested. Get NGS—ideally RNA-based NGS—because some NTRK fusions can be missed if testing is done using only DNA-based methods.

What does the future hold for precision medicine as it relates to targeting NTRK fusions?

We already have another drug [repotrectinib (Augtyro)], which was primarily developed for patients with ROS1-positive lung cancer. [Repotrectinib] can also target some of the resistance mechanisms seen in patients on larotrectinib.

Again, many of these patients will remain on larotrectinib for many months, if not years. However, if they do develop resistance, it typically occurs in specific regions of the NTRK target—what are called solvent-front mutations and gatekeeper mutations. [Repotrectinib] can target those areas.

There are also other agents working their way through the pipeline that may be used in patients who develop resistance to [larotrectinib] as well. There's even data suggesting that combining larotrectinib with EGFR inhibitors may help overcome innate resistance.

The great thing about science is that there’s always another horizon ahead. We continue to push forward to help these patients and find ways to improve these therapies.

References

1. U.S. FDA grants full approval of Vitrakvi (larotrectinib) for adult and pediatric patients with NTRK gene fusion-positive solid tumors. News release. Bayer. April 10, 2025. Accessed May 23, 2025. https://www.bayer.com/en/us/news-stories/approval-of-vitrakvi
2. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. November 26, 2018. Accessed May 23, 2025. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions