Bayer Announces EU Approval of Larotrectinib, the First Tumor-Agnostic Cancer Therapy in Europe

Bayer announced today (September 23) that the European Commission has granted marketing authorization in the European Union (EU) for larotrectinib, a precision oncology therapy. The drug is indicated for the treatment of adult and pediatric patients with solid tumors harboring neurotrophic receptor tyrosine kinase (NTRK) gene fusions, who have locally advanced, metastatic, or surgically unresectable disease, or for whom surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments. As the first oral TRK inhibitor specifically developed to treat tumors with NTRK gene fusions, larotrectinib is the first tumor-agnostic anticancer drug approved in the EU. It has demonstrated high and durable response rates in both adult and pediatric patients with TRK-fusion cancers, including those with central nervous system (CNS) tumors, and has already been approved in the United States, Brazil, and Canada.

“With the approval in Europe of the first tumor-agnostic therapy, European physicians can now employ a precision oncology treatment for patients with tumors harboring NTRK gene fusions, replacing previously less targeted therapeutic approaches. The prevalence of NTRK gene fusions varies across different tumor types, and these rare tumors can occur in both adults and children,” said Professor Jesus Garcia-Foncillas, Professor of Oncology at Autonomous University of Madrid. “Current standard treatments for TRK fusion-positive tumors, such as chemotherapy or immunotherapy, have limited efficacy and may be associated with significant side effects. For patients with TRK fusion-positive tumors treated with larotrectinib, we observe rapid, highly effective, and durable responses regardless of patient age or tumor location, with a safety profile consistent with previous reports and manageable.”

The European Medicines Agency (EMA) approval of larotrectinib was based on a pooled analysis of clinical trial data from 102 patients (93 patients from the primary analysis population and an additional 9 patients with primary CNS tumors). The data sources included a Phase I clinical trial in adult patients, the Phase II NAVIGATE trial in adult and adolescent patients, and the pediatric Phase I/II SCOUT trial. Results from the primary analysis population (n=93) showed an objective response rate (ORR) of 72% (95% CI: 62, 81), including 16% complete responses (CR) and 55% partial responses (PR). In a separate analysis focusing on patients with primary CNS tumors, the ORR was 67% (95% CI: 57, 76), including 15% CR and 51% PR. In the pooled primary analysis (n=102), the median duration of response (mDOR) and median progression-free survival (mPFS) had not been reached at the time of the data cutoff. The duration of response ranged from 1.6+ months to 38.7+ months, with 75% of patients maintaining a response for 12 months or longer. One year after treatment initiation, 88% of patients in the primary analysis population (n=93) were still alive (95% CI: 81, 95). Larotrectinib demonstrated a favorable safety profile, with most adverse events (AEs) being Grade 1 or 2, and only 3% of patients discontinuing treatment due to treatment-related AEs.

TRK fusion cancers are generally rare, with no more than a few thousand cases annually in Europe. They can occur in both children and adults, with varying frequencies across different tumor types. TRK fusion cancers arise from the fusion of an NTRK gene with another unrelated gene, resulting in the production of abnormal TRK proteins. These abnormal proteins, also known as TRK fusion proteins, act as oncogenic drivers and possess constitutive activation properties that lead to sustained overactivation of downstream cell signaling pathways. Regardless of the primary tumor site, these TRK fusion proteins promote cancer growth and metastasis in patients. Larotrectinib is an oral, highly selective TRK inhibitor that has been studied in clinical trials across 29 different histological types of solid tumors, including lung, thyroid, melanoma, gastrointestinal stromal tumors (GIST), colon, soft tissue sarcoma, salivary gland, and infantile fibrosarcoma. This compound demonstrates efficacy in patients of all ages with primary central nervous system (CNS) tumors and brain metastases, irrespective of the pathological type of the primary tumor.

“As the first therapy specifically designed for adult and pediatric patients with TRK fusion cancers, larotrectinib’s approval in the EU marks a significant advancement in the fight against cancer, as it targets the drivers of tumor spread and growth rather than the primary tumor site,” said Mr. Robert LaCaze, Member of the Executive Committee of Bayer Pharmaceuticals and Head of the Oncology Strategic Business Unit. “Cancer treatment is currently undergoing a paradigm shift. With the dawn of this new era of precision oncology, we remain committed to delivering innovative medicines, such as larotrectinib, to help patients and physicians worldwide.”

Only specific assays can identify NTRK gene fusions or TRK fusion proteins, including next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), and immunohistochemistry (IHC). IHC is a useful screening tool; however, it detects the expression of both wild-type TRK proteins and TRK fusion proteins. Therefore, positive results require confirmation by more specific assays, such as next-generation sequencing. Patient eligibility for larotrectinib treatment depends on the presence of NTRK gene fusions in the tumor.