Clinical data from three ongoing larotrectinib (LOXO-101) clinical trials in patients whose tumors harbor tropomyosin receptor kinase (TRK) fusions demonstrating a 76 percent confirmed objective response rate (ORR) across tumor types, were published today in the New England Journal of Medicine after an initial summary presentation at the American Society of Clinical Oncology in 2017.1,2
Larotrectinib received Breakthrough Therapy Designation from the FDA in July 2016, for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments. Larotrectinib appears to deliver consistent and durable responses in TRK fusion patients across all ages with few side effects.
Larotrectinib targets a mutation where two genes join together in what’s known as TRK fusion, leading to the production of proteins that cause cancer growth. It’s rare — about 1 percent of cancers have the anomaly, and it’s seen in 1,500 to 5,000 patients annually in the U.S.
Larotrectinib is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body.
TRK fusions are chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in uncontrolled TRK signaling that can lead to cancer. TRK fusions occur rarely but broadly in various adult and pediatric solid tumors including sarcomas, fibrosarcomas, and gastrointestinal stromal tumors (GIST). TRK fusions can be identified through various diagnostic tests, including targeted next-generation sequencing (NGS), immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescent in situ hybridization (FISH). For more information, please visit www.TRKtesting.com.
Forty-three adult and 12 pediatric patients were enrolled, identified by 15 different lab tests. TRK fusion patients carried primary diagnoses of appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, GIST, infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer, and various sarcomas. One patient had central nervous system (CNS) metastases at study entry. Overall 76 percent of patients responded to treatment and the median survival and time to cancer progression have not been reached. Ninety-three percent of all responding patients either remain on drug or received surgery with curative intent. Seventy-five percent of all patients enrolled either remain on drug or received surgery with curative intent.
The larotrectinib TRK fusion story fulfills the promise of precision medicine, where tumor genetics rather than tumor site of origin define the treatment approach. It is now incumbent upon the clinical oncology and pathology communities to examine our testing paradigms, so that TRK fusions and other actionable biomarkers become part of the standard sarcoma patient workup.
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