The US Food and Drug Administration (FDA) granted accelerated approval to larotrectinib (Vitrakvi, Loxo Oncology) for the treatment of adult and pediatric solid tumors that have a targetable biomarker known as a neurotrophic receptor tyrosine kinase (NTRK) gene fusion.
In effect, the biomarker defines the cancer rather than an organ where the disease originated, as is typically the case.
This is second time the agency has approved a cancer treatment that is based on this new paradigm wherein the drug is “tissue agnostic.”
Previously, pembrolizumab (Keytruda, Merck) was approved for the treatment of solid tumors that are mismatch-repair deficient or that have a high degree of microsatellite instability. However, pembrolizumab had already been approved for many other indications.
Larotrectinib is the first drug to be developed and approved specifically as a tissue agnostic agent. It is indicated for the treatment of solid tumors that have an NTRK gene fusion without a known acquired resistance mutation and are either metastatic or not resectable. Additionally, no satisfactory alternative treatments can be available, or patients must have experienced disease progression following previous treatment.
NTRK gene fusions are rare and occur in cancers arising in many sites of the body, according to the FDA.
Until now, there has been no treatment for some cancers with this genetic anomaly, such as mammary analogue secretory carcinoma, cellular or mixed congenital mesoblastic nephroma, and infantile fibrosarcoma. Other malignancies with possible NTRK gene fusions are more common, such as lung cancer.
“Today’s approval marks another step in an important shift toward treating cancers based on their tumor genetics rather than their site of origin in the body,” said FDA Commissioner Scott Gottlieb, MD, in a press statement.
The efficacy and safety of larotrectinib were studied in three clinical trials that included 55 pediatric and adult patients with solid tumors in which an NTRK gene fusion had been identified and that satisfied other requirements associated with the new approval.
Larotrectinib demonstrated a 75% overall response rate across various solid tumors. The responses were mostly durable, with 73% lasting at least 6 months and 39% lasting a year or longer in the most recent analysis. Tumor types that respond to larotrectinib include soft tissue sarcoma, salivary gland cancer, infantile fibrosarcoma, thyroid cancer, and lung cancer.
According to the FDA, common side effects seen in clinical trials with larotrectinib included fatigue, nausea, cough, constipation, diarrhea, dizziness, vomiting, and increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzyme levels. Healthcare providers are advised to conduct ALT and AST liver tests every 2 weeks during the first month of treatment, then monthly, and later, as clinically indicated.
The approval reflects advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine, Gottlieb said. This type of drug development program was not possible a decade ago because a lot less was known about cancer mutations, he added.
“We’re committed to continuing to advance a more modern framework of clinical trial designs that support more targeted innovations across disease types based on our growing understanding of the underlying biology of diseases like cancer,” Gottlieb declared.
Further clinical trials are required to confirm larotrectinib’s clinical benefit. The sponsor is currently conducting or making plans to conduct these studies, the FDA said.