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U.S. FDA Grants Full Approval of Vitrakvi (larotrectinib) for Adult and Pediatric Patients with NTRK Gene Fusion-Positive Solid Tumors

WHIPPANY, N.J.--(BUSINESS WIRE) April 10, 2025 --Bayer today announced that the U.S. Food and Drug Administration (FDA) has granted full approval for Vitrakvi^® (larotrectinib), a first-in-class TRK inhibitor 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 or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.¹ Vitrakvi has demonstrated clinically meaningful and durable responses across a range of NTRK fusion-positive solid tumors. Vitrakvi was first granted accelerated approval by FDA in November 2018.¹

“This first full approval of an NTRK inhibitor by the FDA represents the culmination of research and dedication by the Bayer team,” said Chandra Goda, Executive Director, U.S. Vitrakvi Brand Lead. “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 Bayer's commitment to delivering innovative solutions that address the unique needs of patients and their families."

"The full approval of Vitrakvi 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, LUNGevity Foundation. "This milestone not only benefits patients today but also paves the way for further advancements in NTRK gene therapies in the future."

This approval is based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). This analysis included pediatric and adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion (n=339). 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.¹ The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. ¹ Safety was assessed in 444 patients across the three trials.¹

Pooled efficacy results showed an ORR of 60% (95% CI: 55%-65%) with a complete response (CR) rate of 24% and a partial response (PR) rate of 36%.¹ Five percent of patients with complete response were pathological complete response. Patients undergoing a surgical resection whose post-operative pathologic assessment showed no viable tumor cells and negative margins were pathological complete responders provided that no other sites of disease were present. Median DOR was 43.3 months (95% CI: 32.5-NE (not evaluable)).¹ The most common (≥20%) adverse reactions, including laboratory abnormalities, with Vitrakvi were increased AST, increased ALT, anemia, hypoalbuminemia, musculoskeletal pain, increased alkaline phosphatase, leukopenia, lymphopenia, neutropenia, hypocalcemia, fatigue, vomiting, cough, constipation, pyrexia, diarrhea, nausea, abdominal pain, dizziness, and rash.¹ Serious adverse events (AEs) reported included central nervous system (CNS) problems, bone fractures and liver problems.¹

About Vitrakvi^® (larotrectinib)

Vitrakvi, a first-in-class oral TRK inhibitor, was exclusively designed to inhibit against the TRK family of proteins (TRKA, TRKB, and TRKC). In in vitro and in vivo tumor models, Vitrakvi 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, promoting cell proliferation and survival in tumor cell lines.¹

In the U.S., Vitrakvi is approved for the treatment of adult and pediatric patients with solid tumors that display a neurotrophic receptor tyrosine kinase (NTRK) gene fusion.¹ Following the acquisition of Loxo Oncology by Eli Lilly and Company in February 2019, Bayer has obtained the exclusive licensing rights for the global development and commercialization, including in the U.S., for Vitrakvi.

INDICATION

Vitrakvi is indicated 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 or where surgical resection is likely to result in severe morbidity, and
• have no satisfactory alternative treatments or that have progressed following treatment.

Select patients for therapy based on an FDA-approved test.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

• Central Nervous System Effects: Central nervous system (CNS) adverse reactions occurred in patients receiving Vitrakvi, including dizziness, cognitive impairment, mood disorders, and sleep disturbances.
  
  In patients who received Vitrakvi, all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 40.3% with Grades 3-4 in 3.8% of patients.
  
  Cognitive impairment occurred in 11% of patients. The median time to onset of cognitive impairment was 6 months (range: 2 days to 56 months). Cognitive impairment occurring in ≥ 1% of patients included memory impairment (4.1%), disturbance in attention (3.6%), confusional state (2.3%), cognitive disorder (1.6%), delirium (1.4%), and hallucination (1.1%). Grade 3 cognitive adverse reactions occurred in 1.8% of patients and Grade 4 cognitive adverse reactions in 0.2% of patients. Among the 49 patients with cognitive impairment, 6% required a dose modification and 18% required dose interruption.
  
  Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.3 months (range: 1 day to 65 months). Mood disorders occurring in ≥1% of patients included anxiety (5%), agitation (3.2%), depression (3.2%), irritability (2.3%), and restlessness (1.1%). Grade 3 mood disorders occurred in 0.9% of patients. Among the 63 patients who experienced mood disorders, no patient required a dose modification, and 1.6% required dose interruption.
  
  Dizziness occurred in 22% of patients, and Grade 3 dizziness occurred in 0.9% of patients. Among the 96 patients who experienced dizziness, 6% of patients required a dose modification and 5% required dose interruption.
  Sleep disturbances occurred in 12% of patients. Sleep disturbances included insomnia (9%), somnolence (3.4%), and sleep disorder (0.5%). Grade 3 sleep disturbances occurred in 0.2% of patients. Among the 54 patients who experienced sleep disturbances, no patient required a dose modification and 3.7% required dose interruption.
  
  Advise patients and caretakers of these risks with Vitrakvi. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue Vitrakvi based on the severity. If withheld, modify the Vitrakvi dosage when resumed.
  
  
• Skeletal Fractures: Skeletal fractures can occur in patients taking Vitrakvi.
  
  Among 444 patients who received Vitrakvi across clinical trials, fractures occurred in 7% of patients; 6% of 290 adult patients and 10% of 154 pediatric patients. Median time to first fracture was 13 months (range 27 days to 73 months) in patients followed per fracture. The most common fractures were of the rib (1.4%), fibula, foot or wrist (0.7% each). Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. Vitrakvi treatment was interrupted due to fracture in 1.4% patients.
  
  Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity). There are no data on the effects of Vitrakvi on healing of known fractures or risk of future fractures.
  
  
• Hepatotoxicity: Hepatotoxicity including drug induced liver injury (DILI) has occurred in patients taking Vitrakvi.
  
  In patients who received Vitrakvi (n=444), increased AST of any grade occurred in 62% of patients and increased ALT of any grade occurred in 61%. Grade 3-4 increased AST or ALT occurred in 7% and 8% of patients, respectively. The median time to onset of increased AST was 1.9 months (range: 4 days to 3.8 years). The median time to onset of increased ALT was 1.9 months (range: 1 day to 4.9 years). Increased AST and ALT leading to dose modifications occurred in 1.6% and 3.2% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 4 (0.9%) patients.
  
  There have been reports from clinical studies and postmarketing cases of Grade ≥ 2 increases in ALT and/or AST with increases in bilirubin ≥ 2 x ULN.
  
  Obtain liver function tests (ALT, AST, ALP and bilirubin) before initiation of Vitrakvi and monitor every 2 weeks during the first 2 months of treatment, then monthly thereafter, or more frequently following the occurrence of Grade 2 or greater AST or ALT elevation. Temporarily withhold, reduce the dose, or permanently discontinue Vitrakvi based on severity.
  
  
• Embryo-Fetal Toxicity: Vitrakvi can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the last dose of Vitrakvi.

Adverse Reactions

• The most common adverse reactions (≥20%), including laboratory abnormalities, were: increased AST (62%), increased ALT (61%), anemia (45%), hypoalbuminemia (44%), musculoskeletal pain (41%), increased alkaline phosphatase (40%), leukopenia (37%), lymphopenia (35%), neutropenia (34%), hypocalcemia (32%), fatigue (31%), vomiting (30%), cough (29%), constipation (27%), pyrexia (26%), diarrhea (26%), nausea (25%), abdominal pain (24%), dizziness (22%), and rash (21%).

Drug Interactions

• Avoid coadministration of Vitrakvi with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the Vitrakvi dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs. For coadministration with moderate CYP3A4 inhibitors, monitor for adverse reactions more frequently and reduce the dosage based on severity. For coadministration with moderate CYP3A4 inducers, modify dose as recommended.

Use in Specific Populations

• Lactation: Advise women not to breastfeed during treatment with Vitrakvi and for 1 week after the last dose.

Please see the full Prescribing Information for Vitrakvi® (larotrectinib).

About TRK Fusion Cancer²

TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing an altered TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade. These TRK fusion proteins act as oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer, regardless of where it originates in the body. TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body. TRK fusion is present in many tumors with varying frequency, including lung, thyroid, gastrointestinal cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).²

TRK fusion cancer is diagnosed through the identification of NTRK gene fusions using specific tests, including those that employ next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH).²

About Oncology at Bayer

Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

About Bayer

Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. In line with its mission, “Health for all, Hunger for none,” the company’s products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2023, the Group employed around 100,000 people and had sales of 47.6 billion euros. R&D expenses before special items amounted to 5.8 billion euros. For more information, go to www.bayer.com.

Forward-Looking Statements

This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

References

1. Vitrakvi^® (larotrectinib) [Package Insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, April 2025.
2. Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK fusions in cancer. Ann Med Surg. 2022;79:103893.

Source: Bayer

Posted: April 2025

Related articles

• FDA Approves Vitrakvi (larotrectinib) for TRK Fusion Cancers - November 26, 2018
• FDA Accepts Larotrectinib New Drug Application and Grants Priority Review - May 29, 2018
• Loxo Oncology Completes Rolling Submission of New Drug Application to U.S. Food and Drug Administration for Larotrectinib for the Treatment of TRK Fusion Cancer - March 26, 2018
• Loxo Oncology Initiates Rolling Submission of New Drug Application to U.S. Food and Drug Administration for Larotrectinib for the Treatment of TRK Fusion Cancers - December 20, 2017

Vitrakvi (larotrectinib) FDA Approval History

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