Larotrectinib: The First Targeted Medicine Approved INDEPENDENTLY OF THE ORGAN Where Cancer Originates

On 26 November 2018, the US Food and Drug Administration (FDA), for a targetable alteration known as neurotrophic receptor tyrosine kinase (NTRK) gene fusion, a mutation present in adult and pediatric solid tumors, granted accelerated approval to the targeted cancer medicine larotrectinib (brand name Vitrakvi) for their treatment.

Thus, as a new biomarker , NTRK gene fusion entered oncology practice. As a biomarker, NTRK provides information about cancer biology rather than the organ where the cancer originated.

This is the 2nd treatment approved by the FDA regardless of the tissue where cancer originated. Previously, in May 2017, the immunotherapy pembrolizumab (Keytruda)received approval for patients with a specific genetic condition [dMMR deficiency or microsatellite instability-high (MSI-H)]. Although larotrectinib is the second tissue-agnostic cancer treatment, it is the first molecularly targeted cancer medicine approved for this purpose.

For a patient with NTRK gene fusion identified by genetic testing to use larotrectinib, they must have metastatic or surgically unresectable cancer, have exhausted other standard treatment options for their cancer, and have experienced disease progression during the previous treatment.

Larotrectinib (Vitrakvi) is an oral pill acting on neurotrophic receptor tyrosine kinase (NTRK) gene fusion.

In some cancer cells, the tropomyosin receptor kinase (TRK) gene joins other genes, resulting in NTRK gene fusion; across all cancers, its frequency ranges from % 0.5 - % 1 , but in some rare cancersit exceeds % 90. Examples include salivary gland cancer, juvenile (childhood or young-age) breast cancer and infantile fibrosarcoma. NTRK positivity can also occur in colon (large bowel), lung, pancreatic and thyroid cancers and melanoma skin cancer.

The efficacy and safety of larotrectinib were evaluated using next-generation sequencing (NGS) or FISH to identify NTRK gene fusion, in 55 pediatric and adult patients across three clinical trials.

Larotrectinib, in various solid tumors, demonstrated an overall response rate of % 75 . Responses were mostly long term; in the latest analysis, responses lasting at least 6 months occurred in % 73, and those lasting one year or longer in % 39. Tumor types responding to larotrectinib included soft tissue sarcoma, salivary gland cancer, infantile fibrosarcoma, thyroid cancer and lung cancer.

According to the FDA, in larotrectinib clinical studies, adverse effects included fatigue, nausea, cough, constipation, diarrhea, dizziness, vomiting and increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzyme levels. Patients are advised to undergo ALT and AST liver testing every two weeks during the first month of treatment and monthly thereafter.

Recommended larotrectinib doses are, for adults, twice daily 100 mg and, for pediatric patients, twice daily (maximum 100 mg per dose) 100 mg / m2.

As our knowledge of cancer biology deepens, and through new-generation clinical trial designs , the number and effectiveness of targeted treatments are increasing. 

Image description: NTRK fusions were first discovered in colon cancer in 1982, but in recent years, technologies such as new DNA sequencing techniques (next-generation sequencing) have made it possible to detect this abnormality in cancer patients. Scientists have now identified more than 50 different genes that fuse with TRK genes. If TRK genes undergo fusion (joining) because of mutation, the resulting abnormal proteins remain constantly "on", signaling cancer cells to grow and multiply.