The oral selective neurotrophic tropomyosin receptor kinase (TRK) inhibitor, larotrectinib (LOXO-101), is well-tolerated and demonstrated “encouraging” anti-tumor activity among infants, children, and adolescents with solid tumors harboring TRK gene fusions, according to findings published in The Lancet Oncology.1

“The efficacy that we have seen is unprecedented,” said lead study author and pediatric hematologist-oncologist Theodore W. Laetsch, MD, of the University of Texas Southwestern Medical Center in Dallas. “There have been durable responses in almost all children, including patients with locally advanced tumors who may have otherwise required an amputation to treat their tumor and patients with chemotherapy-refractory metastatic disease who are unlikely to have survived.”

Fourteen (93%) of 15 pediatric patients whose solid tumors harbored TRK fusions had “sustained tumor regressions.” The remaining patient’s tumor regression did not meet the RECIST criteria for objective response. None of the 7 patients with TRK-negative tumors had objective responses.

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“While I certainly can’t speak for the FDA [US Food and Drug Administration], I do think that approval is very likely without a phase 3 trial,” Dr Laetsch said. “The response rate observed here is unprecedented, and these responses have been durable for most patients. For some children, such as those with recurrent metastatic sarcomas, I believe that a randomized phase 3 trial would be unethical, because the outcomes we have observed with larotrectinib are vastly superior to standard of care. Additionally, larotrectinib has been well-tolerated in both children and adults. The risk/benefit ratio is very favorable.

TRK fusions are very common in some rare pediatric cancers, in particular infantile fibrosarcoma and congenital mesoblastic nephroma, and had been described across a range of other pediatric cancers,” Dr Laetsch added. “Thus, we were very excited to study this drug in children.”

His team did not, furthermore, wait until clinical trials were completed among adults. Because of the drug’s promising safety and efficacy, the first child was treated on trial only 9 months after the first adult with a TRK fusion was treated.

One case of grade 3 alanine aminotransferase elevation in a child with TRK-negative cancer was the only dose-limiting toxicity. Two other drug-related serious adverse events were, however, reported: grade 3 nausea and grade 3 decline in ejection fraction.

“The speed with which this study started in children, and the availability of a liquid formulation so that we could treat very young children who can’t swallow pills, is really unique,” he said.

It’s been a promising model for future studies of experimental treatments of children’s cancers, added Lucas Moreno, MD, PhD, of the Hospital Niño Jesus in Spain, whose commentary on the study was published alongside the study.2

“The investigators and the sponsor developing larotrectinib understood that infants with TRK-positive cancers had a high unmet need and accelerated the development of the drug to open the trial as soon as possible,” he said. “This resulted in a fast opening, fast accruing trial for such a rare indication, and showed an outstanding clinical benefit for children with TRK-positive tumors, not only in terms of radiological responses that were durable but also facilitating non-mutilating surgeries at very young ages.”