Bayer announced that its collaboration partner Loxo Oncology, Inc.,  a biopharmaceutical company based in Stamford, Connecticut (US), has completed the rolling submission of a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for larotrectinib for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. The rolling submission had been initiated in December 2017. NTRK gene fusions are genetic alterations present across a wide range of tumors resulting in uncontrolled tropomyosin receptor kinase (TRK) signaling and tumor growth. Larotrectinib was designed to directly target TRK, turning off the signaling pathway that allows TRK fusion cancer to grow.

“This NDA submission in the US marks an important milestone in bringing us one step closer to providing larotrectinib as a potential treatment option for patients with TRK fusion cancer,” said Scott Fields, MD, Bayer’s senior vice president and head of oncology development at Bayer’s Pharmaceutical Division. “NTRK gene fusions, while rare, are present in various pediatric and adult cancers. We are committed to working with the FDA and the oncology community to bring larotrectinib to patients as soon as possible.”

Bayer and Loxo Oncology are jointly developing larotrectinib, an investigational compound being studied globally for the treatment of patients across a wide range of cancers that harbor an NTRK gene fusion. Bayer plans to submit a Marketing Authorization Application (MAA) in the European Union in 2018.

Larotrectinib is a potent, oral and highly selective tropomyosin receptor kinase (TRK) inhibitor. The investigational new drug is in clinical development for the treatment of patients with cancers that harbor a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. 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. In clinical trials, larotrectinib demonstrated marked and durable anti-tumor activity in TRK fusion cancer regardless of patient age or tumor type. In an analysis of 55 RECIST-evaluable adult and pediatric patients with NTRK gene fusions, larotrectinib demonstrated an 80% investigator-assessed overall response rate (ORR) and a 75% centrally-assessed confirmed ORR, across many different types of solid tumors. Larotrectinib was well tolerated; the majority of all adverse events were grade 1 or 2. There were no treatment-related grade 4 or 5 events, and no treatment-related grade 3 adverse events occurred in more than 5% of patients.

Larotrectinib has been granted Breakthrough Therapy Designation, Rare Pediatric Disease Designation and Orphan Drug Designation by the US FDA.

In November 2017, Bayer and Loxo Oncology entered into an exclusive global collaboration for the development and commercialization of larotrectinib and LOXO-195, a novel TRK inhibitor. Bayer and Loxo Oncology will jointly develop the two products with Loxo Oncology leading the ongoing clinical studies as well as the filing in the US, and Bayer leading ex-US regulatory activities and worldwide commercial activities. In the US Bayer and Loxo Oncology will co-promote the products.

Neurotrophic tyrosine receptor kinase (NTRK) gene 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 tropomyosin receptor kinase (TRK) signaling that can lead to cancer. NTRK gene fusions occur rarely but broadly in various adult and pediatric solid tumors, including 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. NTRK gene fusions can be identified through various diagnostic tests, including targeted next-generation sequencing (NGS), polymerase chain reaction (PCR), fluorescent in situ hybridization (FISH) or by immunohistochemistry (IHC), to detect TRK protein.