1. May, Brandon

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Larotrectinib, a highly selective small-molecule inhibitor of three tropomyosin receptor kinase (TRK) proteins (TRKA, TRKB, and TRKC) has recently been approved by the FDA for TRK fusion cancers. This approval was thanks in part to a new study by researchers at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York City (N Engl J Med 2018;378(8):731-739). Researchers from MSKCC believe this new approval represents a monumental advancement for precision oncology.


"The approval of larotrectinib represents a landmark step," Alexander Drilon, MD, Clinical Director of the Early Drug Development Service at the MSKCC and principal investigator of the NAVIGATE clinical trial (J Clin Oncol 2017; doi:10.1200/JCO.2016.34.15_suppl.TPS2599), told Oncology Times. "For the first time, we have a targeted therapy that is approved for a genomic signature regardless of cancer type. This paves the way for other potential approvals of this nature." Currently, no data have found a significant difference in response to larotrectinib in terms of varying tumor types.


Research Findings

According to the study led by David Hyman, MD, medical oncologist and Chief of the Early Drug Development Service at MSKCC, treatment with larotrectinib was associated with durable antitumor activity in TRK fusion-positive cancer patients. This activity was consistent across all ages and tumor types, suggesting that this therapeutic option may offer additional benefits that weren't explored in this small study with short follow-up.


"The development of targeted therapy in pediatric cancers has traditionally lagged behind its development in adults," Drilon added. "The larotrectinib approval represents an important shift towards including pediatric patients early in drug development. For infants, children, and adolescents, this was particularly important as several cancers in these patients can harbor TRK fusions."


In their study, researchers enrolled a total of 55 patients (age range, 4 months to 76 years) with prospectively identified TRK fusion-positive cancers or 17 unique cancer diagnoses (e.g., tumors of the salivary gland, infantile fibrosarcoma, thyroid, colon, lung, etc.). Patients were included in a phase I study for adults, phase I/II study for children, or phase II study for children and adults. In the phase II study, patients were continuously treated with twice-daily 100 mg oral doses of larotrectinib until either disease progression, study withdrawal, or unacceptable level of adverse events. Overall response rate comprised the primary outcome, whereas duration of response, progression-free survival, and safety made up the secondary endpoints.


The overall response rate at the primary data cutoff date was 75 percent (95% CI, 61-85) and 80 percent (95% CI, 67-90) according to independent review and investigator assessment, respectively. Approximately 86 percent of patients who had a response at the median 9.4-month follow-up had undergone potentially curative surgery or were continuing treatment with larotrectinib. Additionally, the investigators observed no grade 3 or 4 adverse events, and no patients discontinued therapy.


Researchers from MSKCC were able to effectively treat many pediatric cancers, including infantile fibrosarcoma and secretory breast carcinoma. "Cancers driven by TRK fusion mutations are rare," according to a previously published statement made by Neerav (Neal) Shukla, MD, a pediatric oncologist and Director of the Pediatric Translational Medicine Program at MSKCC ( "But because we sequence the tumor genomes of all of our pediatric patients, we are able to identify everyone who might benefit from this drug."


Larotrectinib was initially developed based on basket trials, which study treatments "that act against tumors based on their mutations, regardless of where they develop." These trials are invaluable for studying the effects of cancer treatments on rare carcinomas, particularly those that are rarely assessed in clinical trials. Future trials for these rare cancers have yet to be announced.


Some of the studies' participants became resistant to the effects of larotrectinib over time, specifically when another mutation developed. MSKCC researchers are also studying LOXO-195, another TRK inhibitor that targets this acquired resistance. "Next-generation targeted therapies like LOXO-195 are currently in early-phase clinical trials," Drilon explained. "Some cancers that develop resistance to larotrectinib do so by developing new TRK mutations on top of the original TRK fusion, and these new inhibitors were designed to target these mutations."


Future Directions in Pediatric Cancer

Researchers at MSKCC are also currently working toward building additional early-stage clinical trials and using these data to deliver laboratory discoveries to real-world patients. This initiative, which is a focus of the hospital's Pediatric Translational Medicine Program, is combining efforts of the Early Drug Development Service with the Department of Pediatrics.


Additionally, the Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC), convened by MSKCC, is leading the development of further pediatric oncology trials. Led by Tanya M. Trippett, MD, Pediatric Hematologic Oncologist, the POETIC seeks "to promote the early clinical development of promising therapies for the treatment of children, adolescents, and young adults with cancer and related disorders."


Brandon May is a contributing writer.


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