Larotrectinib for pediatric cancer: New era of genomic medicine

Contemporary PEDS JournalVol 36 No 1
Volume 36
Issue 1

New research is changing views about the treatment of pediatric cancer and bolsters the rationale for sequencing tumors in children.

headshot of Theodore W. Laetsch, MD

Theodore W. Laetsch, MD

headshot of Wendy Allen-Rhoades, MD

Wendy Allen-Rhoades, MD

Results of combined analysis of larotrectinib


Recent approval by the US Food and Drug Administration (FDA) of larotrectinib is a sign of a new era of genomic medicine altering the way cancer typically has been talked about and treated and opening promising possibilities of safer and more efficacious treatment.

Instead of identifying and treating cancer by and at the site of tumor development, genomic medicine identifies and targets genetic mutations underlying cancer regardless of its site of tumor development.

“Larotrectinib is only the second therapy approved by the FDA for the treatment of cancer based on the presence of a genetic mutation regardless of the type of cancer in which the mutation occurs,” says Theodore W. Laetsch, MD, University of Texas Southwestern Medical Center–Children’s Medical Center of Dallas, Texas, and coauthor of several new studies of larotrectinib for TRK fusion-positive cancers.

“This is starting to change how we think about the treatment of cancer and adds to the rationale for sequencing the tumors of children with difficult to treat malignancies,” he says.

Remarkable efficacy: Paradigm shift?

On November 26, 2018, the FDA granted accelerated approval of larotrectinib for treatment of solid tumors with tyrosine kinase (TRK) gene fusion in both adult and pediatric patients. Approval was based on data from multicenter, open-label, single-arm studies that showed the efficacy and safety of larotrectinib in this setting.1-3

Results from a study published in the New England Journal of Medicine that looked at the efficacy of larotrectinib in both adults and children with TRK fusion-positive cancers found an overall response rate of 75% according to an independent review. The results reflect a combined analysis of 3 protocols in which 55 adult and pediatric patients (ranging in age from 4 months to 76 years) with consecutively and prospectively identified TRK fusion-positive cancers (17 unique types) were enrolled into 1 of 3 protocols: a phase I study of adults, a phase I/II study of children, or a phase II study of adolescents and adults.1

All patients in the study had locally advanced or metastatic solid tumor, had been treated previously with standard therapy, and had adequate functioning of major organs. Along with the primary outcome (overall response rate assessed by an independent review), the study looked at secondary endpoints including overall response rate by the investigator, duration of response, progression-free survival, and safety. Overall results of the study are shown in the Table.

A combined analysis also showed the safety of larotrectinib, with grade 1 adverse events predominating (eg, low blood counts, elevations in liver function, and gastrointestinal symptoms) and only 5% of patients experiencing grade 3 or 4 adverse events by investigator assessment. None of the patients discontinued treatment because of adverse events.

“Across children and adults, responses were seen in more than a dozen different tumor types,” says Laetsch. “It didn’t seem to matter what type of cancer the patient had as long as the tumor had a TRK fusion.”

Results in children

Recently published results highlight the safety and efficacy of larotrectinib in children.2 A phase I/II study done to assess the safety of larotrectinib as well as the recommended dose in children found that a dose of 100 mg/m2 (maximum 100 mg per dose) offered significant efficacy and safety regardless of the age of the child.

The study included 24 patients, 17 with tumors harboring TRK fusions and 7 without documented TRK fusions. The patients included infants, children, and adolescents who were enrolled in 3 dose cohorts. Most of the children enrolled in the study with TRK fusion-positive cancers had infantile fibrosarcoma (n=8, 47%), followed by other soft tissue sarcomas (n=7, 41%), and papillary thyroid cancer (n=2, 12%).

The study found that larotrectinib was well tolerated by the pediatric patients, with grade 1 or 2 comprising most of the adverse events (n=21, 88%). “[Adverse] effects of larotrectinib are generally mild, and usually much less than we see with traditional chemotherapy,” says Laetsch, who added that no long-term adverse effects so far have been seen, but the first child with a TRK fusion tumor began treatment with larotrectinib less than 3 years ago.

The study also showed that every child with a TRK fusion solid tumor treated with larotrectinib had tumor shrinkage, with 93% of these patients meeting the criteria for a centrally confirmed objective response, according to Laetsch. An objective response, he notes, was defined as at least 30% shrinkage of the largest tumor diameter measured by an independent radiologist.

In addition, Laetsch emphasizes that the responses seem durable. “Only 1 of 17 children with a TRK fusion cancer in our study developed resistance to larotrectinib,” he says.

Of note, none of the children with TRK fusion-negative cancers had an objective response to larotrectinib.

Wendy Allen-Rhoades, MD, assistant professor, Department of Pediatrics, Section of Hematology–Oncology, Baylor College of Medicine, Texas Children’s Hospital, Houston, highlighted on the remarkable efficacy shown in this study. “This trial shows phenomenal responses, and responses like this in a phase I and II trial are extremely rare,” she says. “I think we all hope in the oncology community that this is where we go as we develop more molecularly targeted therapy for tumors.”

For Allen-Rhoades, these results indicate that a paradigm shift may be close on the horizon for treating TRK fusion solid tumors in children. “I wouldn’t say that the shift has happened, but this is definitely the door for it to swing into this molecularly targeted therapy,” she says.

However, she emphasizes that questions remain, particularly the unknowns about the long-term consequences of the drug and optimal length of therapy. “While we’re really excited as these are some of the best results we’ve seen in a long time, there is always the flip side of it that this is not a magic bullet for everyone,” she says. “There are going to be people this doesn’t work for, there will be people who develop resistance to it, so using it for upfront therapy has to be done thoughtfully.”

Importance of trials that include children

Along with the strong efficacy and safety shown by the trials, both Laetsch and Allen-Rhoades point to another exciting aspect of the trials-their inclusion of children.

“Children were included very early in clinical trials of larotrectinib,” says Laetsch, pointing out that the first child with TRK fusion cancer was treated only 8 months after the first adult.

“This is an example of how early inclusion of children in clinical trials of a new cancer therapy can both benefit children as well as expedite approval of the therapy for both children and adults,” he says.

For Allen-Rhoades, the inclusion of children in these trials is what the pediatric oncology community has been advocating for a long time.

Given the fear of including children in clinical trials because of the potential for toxicity that would kill a drug from being developed, Allen-Rhoades says the importance of the larotrectinib trials shows that including children can be done and in fact helped get FDA approval of the drug.

“I think this trial definitely showed that not only did we not hurt the trial, but in this case including children in the trial helped get FDA approval because they comprised 25% of the patients in the trial,” she says.


For Allen-Rhoades, these trials represent a new era of clinical trials. “If you have a target in an adult and you have that same target in a child, both should be included in the initial testing of the drug,” she says. “This is a pivotal trial that we’ve been waiting for to show that we can do this and do this in a safe way. “It’s all good stuff.”


1. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. Available at: Accessed January 3, 2018.

2. Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicenter, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705-714. Erratum in: Correction to Lancet Oncol. 2018;19:704-714.

3. Laetsch TW, Hawkins DS. Larotrectinib for the treatment of TRK fusion solid tumors. Expert Rev Anticancer Ther. October 23, 2018:1-10. Epub ahead of print.

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