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FDA Approves Larotrectinib for Adult and Pediatric Patients With NTRK Gene Fusion-Positive Solid Tumors
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Key Takeaways
- Larotrectinib received full FDA approval for NTRK gene fusion-positive solid tumors, following its 2018 accelerated approval.
- The treatment demonstrated a 60% overall response rate in clinical trials, with a median duration of response of 43.3 months.
The approval is for those with metastatic disease or in whom surgical resection is likely to result in severe morbidity, have no satisfactory alternative treatments, or have progressed following treatment.
The FDA granted full approval to larotrectinib (Vitrakvi; Bayer HealthCare Pharmaceuticals) for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, in whom surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Initially granted accelerated approval by the FDA in 2018, the treatment has demonstrated both clinically meaningful and durable responses across a plethora of NTRK fusion-positive solid tumors.1
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“This first full approval of an NTRK inhibitor by the FDA represents the culmination of research and dedication by the Bayer team,” Chandra Goda, executive director, US VITRAKVI Brand Lead, said in a news release. “We are proud to deliver on our promise for patients with this significant step forward, providing a treatment option for pediatric and adult patients living with NTRK gene fusion-positive cancers. This milestone reinforces [our] commitment to delivering innovative solutions that address the unique needs of patients and their families."1
Larotrectinib is a first-in-class oral TRK inhibitor that was exclusively designed to inhibit the TRK family of proteins (TRKA, TRKB, and TRKC). In both in vitro and in vivo tumor models, it demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. Constitutively activated chimeric TRK fusion proteins can act as an oncogenic driver and allow for cell proliferation and survival in tumor cell lines.1 The treatment’s approval was supported by data from 3 multicenter, open-label, single-arm phase 3 clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). These pooled data were published in the Journal of Clinical Oncology and presented at the 2023 American Society of Clinical Oncology Annual Meeting.1,2
The analysis included a total of 339 pediatric and adult patients with unresectable or metastatic solid tumors (eg, thyroid, lung, colon, salivary gland, soft tissue sarcoma) with an NTRK gene fusion. All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. The investigators noted that the major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee according to RECIST v1.1. Across the 3 trials, safety was assessed in 444 patients.1,2
Pooled efficacy results demonstrated an ORR of approximately 60% (95% CI 50%–65%) in larotrectinib-treated patients.1 Additionally, there were 29 (16%) complete responses (including 1 pathological complete response), 74 (41%) partial responses, 39 (22%) stable diseases, 23 (13%) progressive diseases, and 15 (8%) who were not evaluable.2
In addition, ORR in 22 evaluable patients with baseline central nervous system (CNS) metastases was 68% (95% CI 45%–86%), according to the investigators.2 The median time to response was about 1.8 months2, and the median DOR was about 43.3 months (95% CI 32.5%–not estimable [NE]).1 Median progression-free survival was 24.6 months (95% CI 11.3–34.5) at a median follow-up of 28.5 months.1
The most common adverse events (AEs) in patients treated with larotrectinib, including laboratory abnormalities, were increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase; anemia; hypoalbuminemia; musculoskeletal pain; leukopenia; lymphopenia; neutropenia; hypocalcemia; fatigue; nausea and vomiting; cough; constipation; pyrexia; diarrhea; abdominal pain; dizziness; and rash. Additionally, serious AEs reported included CNS problems, bone fractures, and liver problems, according to the news release.1
"The full approval of [larotrectinib] by the FDA is a welcome step forward, solidifying its place as a treatment option for patients with NTRK gene fusion-positive cancers," said Andrea Ferris, president and CEO of the LUNGevity Foundation, in the news release. "This milestone not only benefits patients today but also paves the way for further advancements in NTRK gene therapies in the future."1
