David Hyman, MD
Larotrectinib (LOXO-101), an oral inhibitor of tropomyosin receptor kinases (TRKs), is being developed in a novel multifaceted clinical trial program that spans cancer types and age groupings and is helping to set the pace for an emerging tumor-agnostic drug development paradigm.
The program consists of 3 clinical trials that are recruiting adult, adolescent, and pediatric patients with advanced solid tumors: a phase I trial, the phase II NAVIGATE trial, and the phase I/II SCOUT trial (Table). The studies are seeking to assess the safety and efficacy of larotrectinib as a monotherapy in patients who have exhausted all other standard-of-care options. Each trial is a single-arm study and will accept patients with any advanced solid tumor, although patients must have a confirmed NTRK1
, or NTRK3
Table. Clinical Trials in the Larotrectinib Development Program. (Click to enlarge image)
“One of the unique features of the entire program is that these individual studies operated seamlessly as one unified development effort,” said David Hyman, MD, a medical oncologist and chief of the early drug development service at Memorial Sloan Kettering Cancer Center in New York City. “It included patients from very young children all the way to elderly adults from its onset. The other unique aspect is the histology or tumoragnostic approach; any patient with any tumor type is allowed on this program.”
Hyman is the primary investigator for the NAVIGATE trial and is the head of the larotrectinib trial program.
Rationale for Targeting TRK
, and NTRK3
genes encode the TRKA, TRK B, and TRK C proteins, respectively. These receptors play a key role in the development of the central and peripheral nervous systems. According to Hyman, these proteins have a limited role in normal tissue biology after embryologic development in the function of the central nervous system: TRK A is primarily associated with the development of pain sensation and thermoregulation; TRK B is involved in movement, memory, mood, and weight homeostasis; and TRK C is associated with proprioception.1
However, in cancer each can undergo a chromosomal rearrangement that can promote high expression and activation of the TRK kinase domain.1
TRK fusions occur in a number of diverse cancer histologies, including adult and pediatric cancers. In more common cancers, such as lung, colon, and breast, TRK fusions are rare, occurring at a rate of 0.5% to 1% of cases. In several rare cancer types, however, including infantile fibrosarcoma, secretory breast cancer, and mammary analog secretory carcinoma of the salivary gland, TRK fusions are defining molecular aberrations and are present in most cases.1
Larotrectinib is the first small-molecule pan-TRK inhibitor in development that is 1000-fold selective. It only inhibits 3 kinases, TRK A, TRK B, and TRK C. This turns off the signaling pathway that allows TRK fusion-involved cancers to grow.2
“The idea is that it wouldn’t matter where the tumor arose,” said Hyman. “If [TRK fusions] were found in the cancer, the cancer would be reliant on them and it would be responsive to a TRK inhibitor.”
For this reason, according to Hyman, identifying patients who are positive for TRK fusions could constitute a new cancer diagnosis. “We essentially group cancers based on where they came from, because that has been historically useful in selecting therapy and studying them, but TRK fusion– positive cancers [act as] a diagnostic entity because they predict response to a drug and therefore it’s potentially a more useful diagnostic classification than saying it’s a sarcoma or breast cancer,” he said.