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Larotrectinib, an oral inhibitor of tropomyosin receptor kinases, is being developed in a novel multifaceted clinical trial program that spans cancer types and age groupings.
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, NTRK2, or NTRK3 gene fusion.
“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.NTRK1, NTRK2, 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.
The drug could provide a new standard of care for patients who have very few, if any, treatment options left. “In this program, there were a small number of patients treated on a neoadjuvant basis and as a result of that were able to have minimal, limb-sparing surgeries, and are off-drug and in remission. It’s another interesting aspect of this—the use of targeted therapies to facilitate surgical cures with minimizing morbidity, which is especially important in children who will have potentially decades ahead of them,” Hyman said.Larotrectinib has demonstrated high efficacy and a tolerable safety profile across a range of solid tumors. In a report of findings from the phase I SCOUT trial at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, larotrectinib induced a 92% objective response rate (ORR) for 13 patients with TRK fusions.3 The overall study included patients who ranged in age from younger than 1 year to older than 12 years.
“Every child with a TRK fusion had tumor shrinkage, with all but 1 showing a RECIST response to therapy,” said Theodore W. Laetsch, MD, an assistant professor at the University of Texas Southwestern Medical Center in Dallas, when presenting the data at ASCO. “While this is a phase I study, this response rate is really unprecedented.”
In this assessment, the most common adverse events (AEs) included nausea, increased aspartate aminotransferase, neutropenia, anemia, and constipation. AEs were generally mild, mostly grade 1 or 2, and no grade 4 AEs were observed.3 Combined data from the first 55 patients enrolled in the larotrectinib program showed an ORR by investigator assessment of 76%, including a partial response (PR) rate of 64% and a complete response (CR) rate of 12%. Five additional patients who joined the study too early to have had their confirmatory scans all had at least a PR to larotrectinib.1
The participants comprised adult and pediatric patients with advanced solid tumors representing 17 unique cancer types (Figure).1 In updated results announced in October, the ORR for these patients by independent review was 75% (95% CI, 61%-85%), consisting of a 13% CR and a 62% PR. The investigator-assessed ORR was 80% (95% CI, 67%-90%), with a 16% CR and a 64% PR.4 Similar to the SCOUT trial, the drug has been very well tolerated, with reports of low-grade fatigue, dizziness, nausea, and constipation, with no grade 4 AEs observed.1
“One of the things that makes TRK an attractive target for treating cancer is its limited role outside the cancer,” said Hyman. “Patients tolerate it extremely well, and it makes chronic long-term dosing feasible. We see patients now on the drug approaching 3 years with excellent tolerance.”
Larotrectinib has a breakthrough therapy designation from the FDA for adult and pediatric advanced solid tumors harboring a TRK fusion who have either progressed on or have no existing standards of care.5
Loxo Oncology, Inc, which is developing the drug, plans to seek regulatory approvals for larotrectinib from the FDA and the European Medicines Agency.4
In addition to developing larotectinib, researchers are exploring methods of testing for TRK fusions. Currently, there are 3 modalities for testing for TRK fusions that have varying potential for use as diagnostics in this space: fluorescence in situ hybridization, immunohistochemistry (IHC), and next-generation sequencing.
Loxo Oncology is partnering with Ventana Medical Systems, a member of the Roche Group, to develop a pan-TRK fusion IHC test as a companion diagnostic for larotrectinib.