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Larotrectinib induces durable response in TRK fusion-positive pediatric cancer
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Larotrectinib showed antitumor activity among infants and children with tropomyosin receptor kinases, or TRK, fusion-positive cancers, according to results of a phase 1 dose-escalation study.
The drug also appeared to be well tolerated with minimal toxicities.
“In some cancers, a part of the TRK gene has become attached to another gene,” Theodore W. Laetsch, MD, assistant professor of pediatrics at Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, said in a press release. “When this occurs, it leads to the TRK gene being turned on when it’s not supposed to be and that causes the cells to grow uncontrollably.”
Larotrectinib (LOXO-101, Loxo Oncology) is a highly selective inhibitor of TRK kinases.
“What’s unique about the drug is it is very selective; it only blocks TRK receptors,” Laetsch added.
Although TRK fusions are uncommon in adult malignancies and pediatric cancers, they occur at a higher rate among various rare pediatric tumors such as infantile fibrosarcoma and papillary thyroid cancer.
HemOnc Today previously reported that larotrectinib showed promising activity among adults with certain TRK-fusion positive cancers.
The FDA granted orphan drug designation to larotrectinib for the treatment of solid tumors with neurotrophic TRK fusion proteins in May 2017.
Laetsch and colleagues aimed to further evaluate the role of TRK inhibition for pediatric patients.
The evaluation included 24 patients aged up to 21 years (median age, 4.5 years; range, 1 month-18 years) whose tumors harbored TRK fusions (n = 17) or who had no documented TRK fusion (n = 7). Of those with TRK fusions, nine involved NTRK1, one involved NTRK2 and seven involved NTRK3.
All patients had relapsed, progressed or were nonresponsive to available therapies regardless of TRK fusion status; a Karnofsky or Lansky performance status score of 50 or higher; adequate organ function; and complete recovery from previous anticancer therapies’ toxicities.
Eight patients had infantile fibrosarcoma, seven had soft tissue sarcoma and two had papillary thyroid cancer.
Researchers divided patients into three dosing cohorts: 100 mg or 150 mg larotrectinib twice daily based on age and bodyweight to achieve an area under the curve (AUC) the same as adult doses, or 100 mg/m2 twice daily — regardless of age — that matched up to 173% of the recommended phase 2 dose for adults.
Safety, including dose-limiting toxicity, served as the primary endpoint. Secondary endpoints included maximum tolerated dose, pharmacokinetics, antitumor activity, objective response rate, PFS, OS, and pain and health-related quality-of-life assessments.
The median follow-up was 5.6 months (interquartile range, 1.6-9.2).
Most adverse events (88%) were grade 1 or 2. The most common treatment-related events of all grades included alanine and aspartate aminotransferase elevation (42%), leucopenia (21%), lower neutrophil count (21%) and vomiting (21%).
One patient without TRK fusion-positive disease experienced dose-limiting grade 3 alanine aminotransferase increase.
Serious adverse events included grade 3 nausea and ejection fraction decrease after treatment discontinuation and while on anthracyclines.
The maximum tolerated dose was not reached. Researchers recommended a maximum 100-mg/m2 dose for infants, children and adolescents in phase 2 trial evaluation.
Fourteen patients (93%; 95% CI, 68-100) with TRK fusions had objective response per RECIST criteria, which included four complete responses and 10 partial responses. An initial partial response in one patient turned to stable disease at a subsequent assessment.
“Every patient with a TRK fusion-positive solid tumor treated on this study had their tumor shrink,” Laetsch said in the release. “The nearly universal response rate seen with larotrectinib is unprecedented.”
Larotrectinib may be a new therapeutic option for patients with locally advanced TRK fusion-positive disease otherwise facing disfiguring surgery, the researchers wrote.
The absence of neurological toxicities was remarkable, but further validation is needed, Lucas Moreno, MD, PhD, of the clinical trials unit at Hospital Infantil Universitario Niño Jesús in Madrid, wrote in an accompanying editorial.
“Given that these patients have a potential long-term risk [for] delayed central nervous system toxicities, long-term follow-up is key to have conclusive data on neurological toxicities,” Moreno wrote.
Still, the study by Laetsch and colleagues is a “major breakthrough” due to the biological rationale supporting larotrectinib development, clinically meaningful activity and durable responses, according to Moreno.
“This phase 1 trial showed short-term safety and encouraging activity of larotrectinib in pediatric patients with solid tumors harboring NTRK fusions and is an exemplary study design in terms of biological rationale, rapid accrual and inclusion of pediatric age cohorts, which maximizes its chances of success and paves the way for development of other targeted agents in childhood cancers,” he wrote. – by Melinda Stevens
Disclosures: Laetsch reports advisory board and consultant roles with Eli Lilly, Loxo Oncology and Novartis, as well as research funding to his institution from Pfizer. Please see the full study for a list of all other authors’ relevant financial disclosures. Moreno reports no relevant financial disclosures.
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