The European Commission has granted marketing authorization in the European Union ( EU ) for the precision oncology treatment Vitrakvi ( Larotrectinib ).
The drug is indicated for the treatment of adult and pediatric patients with solid tumors that display a Neurotrophic Tyrosine Receptor Kinase ( NTRK ) gene fusion, who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory treatment options.
Vitrakvi, a first-in-class oral TRK inhibitor exclusively designed to treat tumors that have an NTRK gene fusion, is the first treatment in the EU to receive a tumor-agnostic indication.
Vitrakvi has demonstrated high response rates and durable responses in adults and children with TRK fusion cancer, including central nervous system ( CNS ) tumors.
The EMA approval of Vitrakvi is based on pooled clinical trial data of 102 patients ( 93 patients from the primary analysis population and an additional 9 patients with primary CNS tumors ) across the phase I trial of adult patients, the phase II NAVIGATE trial in adult and adolescent patients and the phase I/II pediatric SCOUT trial.
Results in the primary analysis population ( n=93 ) have demonstrated an overall response rate ( ORR ) of 72% ( 95% CI: 62, 81 ) including 16% complete responses ( CR ) and 55% partial responses ( PR ).
In an additional analysis including primary CNS patients, the ORR was 67% ( 95% CI: 57, 76 ) including 15% CR, and 51% PR.
In the pooled analysis set ( n=102 ), neither the median duration of response nor median progression free survival had been reached at time of analysis. Responses ranged from 1.6+ to 38.7+ months and 75% of responding patients had a duration of response of 12 months or longer.
At one year after the start of therapy, 88% ( 95% CI: 81, 95 ) of patients from the primary analysis population ( n=93 ) were still alive.
The safety of Larotrectinib was evaluated in 125 patients with an NTRK gene fusion. Larotrectinib showed a favorable safety profile, with the majority of adverse events being grade 1 or 2.
Only 3% of patients had to stop therapy due to treatment-emergent adverse reactions.
TRK fusion cancer is rare overall, affecting no more than a few thousand patients across Europe annually. It affects both children and adults and occurs in varying frequencies across various tumor types.
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 that fuel the spread and growth of the patients’ cancer, regardless of where it originates in the body.
Larotrectinib, an oral, highly selective TRK inhibitor, was investigated in clinical trials across 29 different histologies of solid tumors including lung, thyroid, melanoma, gastrointestinal stromal tumors, colon, soft tissue sarcomas, salivary gland and infantile fibrosarcoma.
The drug has shown efficacy in primary CNS tumors as well as patients with brain metastases, across age or tumor histology.
Only specific tests can identify NTRK gene fusions or TRK fusion proteins, these include next generation sequencing ( NGS ), flourescense in situ hybridization ( FISH ), reverse transcription polymerase chain reaction ( RT-PCR ) and Immunohistochemistry ( IHC ).
IHC is a useful screening tool. However, IHC detects both the expression of the wildtype TRK protein as well as the TRK fusion protein; therefore, positive results need to be confirmed by more specific tests such as next-generation sequencing.
Patients eligible for treatment with Vitrakvi should be selected based on the presence of an NTRK gene fusion in their tumor. ( Xagena )
Source: Bayer, 2019