Advancing the treatment of NTRK-fused pediatric solid tumors: lessons from the ADVL1823 study

The manuscript entitled “Larotrectinib for Newly Diagnosed Infantile Fibrosarcoma and Other Pediatric NTRK Fusion-Positive Solid Tumors (Children’s Oncology Group ADVL1823)” not only adds to the growing body of evidence supporting larotrectinib’s efficacy and safety but also underscores the transformative potential of tissue-agnostic targeted therapy in pediatric oncology (1).

Fusions of NTRK1, NTRK2, or NTRK3 most commonly arise from rearrangements with unrelated partner genes, constituting the principal oncogenic alteration within this family. The resulting chimeric protein retains constitutive activation or is aberrantly overexpressed, acting as a critical driver of tumor initiation and progression. Larotrectinib is a small-molecule inhibitor with highly selective activity against NTRK fusions, regardless of whether the alteration involves NTRK1, NTRK2, or NTRK3 (2). Historically, pediatric solid tumors have been classified and managed according to histology and anatomical sites. More recently, the recognition of tumor-enriched histologies harboring NTRK fusions, together with the availability of targeted therapies using selective molecules, has transformed clinical outcomes and established precision medicine as a promising opportunity to address challenging oncologic scenarios (3). The Children’s Oncology Group ADVL1823 trial exemplifies how molecular profiling and the identification of actionable targets can alter this paradigm, moving us toward biology-driven treatment strategies. Particularly in infantile fibrosarcoma (IFS), a tumor type highly enriched for NTRK fusions in which standard surgery can lead to significant morbidity, larotrectinib represents a paradigm shift by enabling effective, less invasive, and potentially organ-preserving and limb-sparing approaches (4,5).

Equally compelling is the demonstration of tissue-agnostic activity, providing important insights into the role of highly selective TRK inhibition in the treatment of children with NTRK fusion-positive malignancies (6). The study enrolled two histology-based cohorts: Cohort A (n=18) comprised exclusively patients with IFS, whereas Cohort B (n=15) included children with NTRK fusion-positive tumors such as inflammatory myofibroblastic tumor (IMT), low-grade glioma (LGG), different types of NTRK-rearranged spindle cell tumors (malignant tumor, spindle cell type; spindle cell sarcoma; and malignant mesenchymoma), and congenital mesoblastic nephroma (CMN). Of interest, the results from ADVL1823 highlight not only the durability of response but also the rapidity and breadth of clinical benefit. Importantly, it suggests the potential of larotrectinib to help convert some initially unresectable lesions into tumors that may become surgically manageable. This is of relevance, as it emphasizes the critical importance of achieving local control, especially in cases of IFS.

Of note, the use of larotrectinib to treat NTRK-fused solid tumors of different histologies consistently shows very favorable overall response rates (ORRs), event-free survival (EFS), and overall survival (OS) (7-9). In ADVL1823, the ORR for IFS was 94% [n=17/18 cases; 95% confidence interval (CI): 72.7% to 98.6%] in up to six cycles and around 60% (n=9/15 cases; 95% CI: −32.3% to 83.7%) for tumors of different histologies. Additionally, the 2-year EFS was 82.2% (95% CI: 54.3% to 93.9%) for IFS and 80% (95% CI: 50.0% to 93.1%) for other tumors, while the 2-year OS was 93.8% (95% CI: 63.2% to 99.1%) for IFS and 93.3% (95% CI: 61.3% to 99.0%) for other tumors. Importantly, outside the setting of controlled clinical trials, a few real-world studies have also confirmed the efficacy of larotrectinib in treating children with NTRK fusion-positive solid tumors (10,11).

Two additional findings from the ADVL1823 study deserve emphasis: the potential for re-exposure to larotrectinib while maintaining a favorable response, and the consistently favorable tolerability profile in a population uniquely vulnerable to treatment-related toxicities. Regarding adverse effects, the pivotal study by Drilon et al. found that most events were grade 1 or 2, with no serious adverse effects related to larotrectinib, and no treatment discontinuations due to drug-related toxicity (7). For children, minimizing long-term adverse effects is as crucial as achieving remission, and this agent exemplifies how targeted therapies can contribute to both objectives. Nevertheless, as most patients enrolled in ADVL1823 were very young, with a median age of 8 months, it will be essential to follow this cohort prospectively to monitor for potential late or as yet unrecognized adverse events that may emerge with prolonged exposure to larotrectinib. In addition, the ADVL 1823 study investigated the concept of finite treatment duration. This approach has also been explored in other clinical studies (12), and it may be particularly relevant for the pharmacoeconomic sustainability of incorporating larotrectinib into health systems. This is especially important in countries with heterogeneous resource availability for precision medicine treatments and initiatives. Nevertheless, challenges remain. Access to broad molecular testing is uneven, particularly in resource-limited settings, and timely identification of NTRK fusions is essential if patients are to benefit from TRK inhibitors. Furthermore, additional molecular studies are needed to identify specific biomarkers for subgroups of patients, such as those who develop drug resistance or who exhibit atypical response patterns, for example, patients who, even without local control, remained free of new events. A more challenging issue relates to access to therapy, particularly for children with cancer living in low- and middle-income countries, which account for nearly 80% of all pediatric cancer cases worldwide (13). Despite regulatory approvals of larotrectinib by agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), real-world access to this medication outside well-developed countries remains limited and difficult. An important achievement to be celebrated is the recent approval (August 2025) of larotrectinib in Brazil by CONITEC (National Committee for Health Technology Incorporation). This milestone will allow the drug to be provided through the Brazilian National Health System (SUS) to all children diagnosed with NTRK fusion-positive cancers that are locally advanced or metastatic in Brazil. This represents not only a significant step toward improving clinical outcomes for affected children, but also an opportunity to build global expertise in the use of larotrectinib in larger real-world scenarios.

In conclusion, this trial provides compelling evidence that larotrectinib should be considered as a frontline option for newly diagnosed IFS and some NTRK fusion-positive pediatric tumors. More broadly, it serves as a model for how precision medicine can and should be integrated into pediatric oncology practice. The lessons from ADVL1823 extend beyond a single drug or pathway: they reflect a broader commitment to biology-driven, patient-centered innovation that offers real hope for children with cancer.

Acknowledgments

We would like to thank the Brazilian Committee of Precision Medicine in Pediatric Oncology (BC-PMPO) and the Brazilian Society of Pediatric Oncology (SOBOPE) for their valuable support and contributions to this work. This manuscript was reviewed for grammar and language consistency using ChatGPT (OpenAI, GPT-5). All authors take full responsibility for the content of this manuscript.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Pediatrics. The article has undergone external peer review.

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-572/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-572/coif). C.S.C.V. reports consulting and advisory role in Bayer. E.T.V. reports consulting or advisory role in Pfizer and Bayer. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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