Outcomes of elective discontinuation, retreatment, and alternatives to surgery in childhood fibrosarcoma

The discovery of tropomyosin receptor kinase (TRK) oncogenes dates back to 1975 (1), when it was first demonstrated that the src oncogene—responsible for tumorigenesis induced by the Rous sarcoma virus—originated from a cellular gene in the chicken genome transduced by the virus. This seminal finding laid the foundation for modern oncogene research and was recognized with the Nobel Prize in Physiology or Medicine in 1989.

The first human oncogene identified was H-RAS, named in honor of Dr. Janet Harvey (“H”) and “Rat Sarcoma” (“RAS”). In 1982, the neurotrophic receptor tyrosine kinase 1 (NTRK1) gene was characterized as an oncogene by Dr. Mariano Barbacid’s laboratory (2,3), leading to the subsequent identification of NTRK2 (TRKB) and NTRK3 (TRKC) as members of the same receptor family (4). These TRK receptors bind neurotrophins with high affinity: TRKA to nerve growth factor (NGF), TRKB to brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4), and TRKC to neurotrophin-3 (NT-3) (5,6).

The ETV6-NTRK3 gene fusion is considered virtually pathognomonic for several pediatric and adult malignancies, including secretory breast carcinoma, mammary analogue secretory carcinoma, congenital mesoblastic nephroma, and infantile fibrosarcoma, with a prevalence exceeding 90% in the latter (7,8) (Table 1).

Larotrectinib is a highly selective, orally administered small-molecule inhibitor of TRK proteins. It exerts its antitumor effects by blocking downstream signaling pathways including MAPK, PI3K-AKT, PKC, and STAT3 (9-11). In November 2018 and September 2019, larotrectinib received regulatory approval in the United States and European Union, respectively, for the treatment of adult and pediatric patients with solid tumors harboring NTRK gene fusions that are locally advanced or metastatic, or for whom surgical resection would likely result in severe morbidity and no satisfactory alternative treatment options exist.

Pivotal clinical trials demonstrated a favorable safety profile and rapid clinical responses, with an overall response rate of 79% [95% confidence interval (CI): 72–85%] across both adult and pediatric populations. The most common grade 3 or 4 adverse events included elevated transaminases, anaemia, and neutropenia. Importantly, no treatment-related deaths were reported (11,12).

Despite these promising outcomes, key clinical questions remain regarding the optimal duration of larotrectinib therapy, criteria for elective discontinuation, and its potential role as neoadjuvant therapy to reduce or eliminate the need for surgery. Data from the SCOUT (NCT02637687) and NAVIGATE trials (NCT02576431) suggest that elective discontinuation may be feasible in selected pediatric patients (13,14). In cases of disease recurrence following cessation, re-initiation of larotrectinib has been shown to restore therapeutic response (Figure 1).

Figure 1 Mechanism of action and clinical management of pediatric NTRK fusion-positive tumors treated with larotrectinib. This figure illustrates the oncogenic mechanism driven by NTRK1, NTRK2, or NTRK3 gene fusions, leading to constitutive activation of TRK signaling pathways that promote tumor cell survival, differentiation, and proliferation. Larotrectinib selectively inhibits TRK proteins, resulting in tumor regression in children with unresectable or metastatic disease. In selected patients achieving complete remission, particularly those who are asymptomatic, in good general condition, and with tumors in non-high-risk anatomical sites, elective treatment discontinuation may be considered to reduce cumulative toxicity and preserve quality of life, provided that close radiologic monitoring is maintaining. Additionally, in cases of relapse, re-initiation of larotrectinib remains highly effective is restoring disease control, whereas treatment discontinuation is indicated for non-response or unacceptable toxicity. NTRK, neurotrophic receptor tyrosine kinase; TRK, tropomyosin receptor kinase.

This area of investigation is critical for identifying risk factors associated with post-treatment relapse. Pathological complete remission has emerged as a potential biomarker for progression-free survival. Although the risk of tumour progression without surgery is approximately 25%, re-treatment with larotrectinib has achieved disease control in the majority of cases. A “wait-and-see” strategy may be appropriate for paediatric or adolescent patients who are asymptomatic, in good general condition, and have tumours located in non-high-risk anatomical sites. This approach allows for therapeutic de-escalation and minimizes cumulative toxicity, particularly neurological and growth-related effects in children. In such cases, regular imaging every 3 months is essential to detect early progression and promptly resume therapy.

In a pooled analysis of the SCOUT and NAVIGATE trials, 47 patients underwent elective discontinuation of larotrectinib. Of these, 16 experienced disease progression after a median of 6 months (15). All 16 were re-treated, with 15 (94%) regaining disease control and 11 achieving partial responses. No unexpected toxicities were observed upon re-treatment.

Elective discontinuation of larotrectinib may reduce long-term drug exposure and improve quality of life in paediatric patients who achieve pathological complete remission or sustained stable disease (≥12 months) (16,17). Close monitoring remains essential, and re-initiation of therapy upon relapse continues to be highly effective. However, the optimal timing and duration of therapy, as well as long-term risks of progression, remain to be fully elucidated.

In summary, larotrectinib represents a safe and effective targeted therapy for NTRK-driven unresectable or metastatic tumours. In the context of infantile fibrosarcoma, it offers a compelling alternative to upfront surgery and conventional chemotherapy, particularly in cases where surgical morbidity is a concern (18-20).

Acknowledgments

We are especially grateful to those patients, their families and researchers whose generosity and capacity to see beyond have allowed many scientific advances to beat paediatric cancers.

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-aw-801/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-801/coif). The authors have no conflicts of interest to declare.

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