By Lynda Williams, medwireNews Reporter
medwireNews: Children who respond to larotrectinib therapy for sarcoma with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion may be able to discontinue treatment, indicates research published in the Journal of Clinical Oncology.
“The larotrectinib wait-and-see analysis results suggest that there is a subset of patients who maintain durable remissions off treatment”, say Leo Mascarenhas (Cedar Sinai Medical Center, Los Angeles, California, USA) and co-investigators.
“For those who had tumor progression after treatment was withheld, the clinical benefit noted on resumption of larotrectinib is encouraging.”
The study follows findings from the ADVL1823 trial of larotrectinib, a tropomysin receptor kinase (TRK) inhibitor, which reported an objective response rate (ORR) of 94% for 18 patients with a new diagnosis of NTRK fusion-positive infantile fibrosarcoma and 60% for 15 patients with other solid paediatric tumours.
Julia Glade Bender (Memorial Sloan Kettering Cancer Center, New York, USA) says in a linked editorial that “these prospective studies provide evidence supporting adaptation of a new consensus treatment paradigm for NTRK fusion-driven pediatric malignancies”.
The current study reports the outcome of 91 children who participated in the SCOUT or NAVIGATE clinical trials assessing the efficacy of larotrectinib for infantile sarcoma (54%), other soft tissue sarcoma or related mesenchymal tumours (STS; 45%) and bone sarcoma (1%). Treatment duration ranged from 1 month to over 87 months, report Mascarenhas et al.
The ORR was 87% and this included a complete response in 52%, with a pathological complete response reported in 13 patients, a partial response in 35% and stable disease in 8%. A further 3% of patients experienced disease progression and 2% were not evaluable.
The investigators explain that 47 of the SCOUT participants who underwent resection or had a nonsurgical complete or partial response or stable disease for at least 2 years discontinued larotrectinib therapy and entered a wait-and-see phase of the study with close follow-up.
This included 30 children with infantile fibrosarcoma and 17 with STS, all of whom had a diagnosis of locally advanced (83%) or metastatic (17%) disease. Larotrectinib was discontinued after a median of 14.7 months overall, 17.2 months in the infantile sarcoma group and 9.0 months in the STS group. Almost half (45%) of these patients underwent an R0, R1 or R2 resection and ended treatment after a median 6.9 months, while the remainder continued treatment for a median 19.8 months and achieved a complete or partial resection or stable disease before discontinuing.
Mascarenhas and co-authors report that 34% of patients experienced disease progression after choosing to discontinue larotrectinib, with progression occurring within 3 months in nine children and within 3–6 months in three, while one child developed progression between 12 and 17 months after discontinuation, and another after more than 24 months.
After a median 41.3 months, the median time to progression was unreached overall and in both the surgical and nonsurgical patients, and this was also true for children with infantile fibrosarcoma and those with STS, the researchers emphasize.
Larotrectinib therapy was restarted in 16 children who relapsed or progressed during the wait-and-see phase after a median of 3.9 months; 69% of these patients experienced an OR, with five complete and six partial responses reported, and four children achieved stable disease. One child underwent surgery after reinitiation and their best response was “undefined”, the team explains.
“All patients in the wait-and-see cohort were alive at the [data] cutoff”, the researchers say.
“This suggests that patients with localized completely resected tumors can discontinue larotrectinib and surgical local control should be strongly considered as soon as feasible without significant morbidity after response to larotrectinib.”
They continue: “Moreover, elective discontinuation with close monitoring after prolonged disease response, even without surgical local control, could potentially be considered in some patients. However, longer follow-up is necessary to determine the optimal length of therapy to allow for larotrectinib discontinuation in this group.”
Commenting on the findings, Bender adds: “Although it is true that the transformational effects of larotrectinib will benefit a limited group of our youngest patients, those patients will go on to live many decades of life with minimal burden from previous cancer therapies.
“Furthermore, the initial recognition of the potential impact on children, early inclusion of the very young in first-in-human studies using an appropriate formulation, and the parsimonious use of rare patients in seamless, longitudinal trials are exemplary of optimally efficient pediatric drug development”, she concludes.
News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of the Springer Nature Group
J Clin Oncol 2025; doi:10.1200/JCO.24.00848
J Clin Oncol 2024; doi:10.1200/JCO-24-01854
J Clin Oncol 2025; doi:10.1200/JCO-24-01854
https://pubmed.ncbi.nlm.nih.gov/39869835