Larotrectinib reduces morbidity, need for aggressive therapies in children with IFS

In the EPI-VITRAKVI study, the TRK* inhibitor larotrectinib reduces morbidity and the need for aggressive local therapies in children with infantile fibrosarcoma (IFS) compared with the current standard of care (SoC).

 

“[U]sing real-world data as a control arm with a robust methodological approach, [our study] demonstrated that larotrectinib prolonged the time to medical treatment failure, reduced the need of subsequent systemic aggressive therapy, and possibly reduced the need for aggressive local tumour treatment,” said Dr Daniel Orbach from Siredo Oncology Center, Institut Curie, Paris, France, at ESMO Sarcoma and Rare Cancers 2023.

 

Orbach and his team conducted a retrospective observational study to evaluate the therapeutic benefit of larotrectinib over the current SoC in this patient setting. Of the 93 participants, 51 were larotrectinib recipients from the SCOUT trial (mean age at index date 2.01 years, 59 percent male). The other 42 patients (mean age at index date 0.73 years, 64 percent male), which were extracted from two** external historical cohorts of patients receiving a chemo-based regimen, comprised the control arm. [ESMO Sarcoma and Rare Cancers 2023, abstract 44O]

 

Only four patients in the larotrectinib arm reported an early medical treatment failure event: two had to start a new systemic treatment, while the other two underwent mutilating surgery. In the control arm, the corresponding rate was 15: six new systemic treatments, five mutilating surgeries, two radiation therapies, and two deaths.

 

Time to medical treatment failure*** was significantly longer in the larotrectinib vs the control arm, both in the unweighted (p log-rank test=0.0023) and weighted analyses (p log-rank test=0.0161). The respective hazard ratios (HRs) for the unweighted and weighted samples were 0.21 (p=0.0058) and 0.15 (p=0.0004).

 

When stratifying by IRS^# group stage, the weighted HR was 0.20 (p=0.0060). “[This] corresponds to an 80-percent lower likelihood of experiencing a medical treatment failure in the larotrectinib arm,” explained Orbach.

 

“[Taken together,] these results indicate the robustness of the primary analysis and were in favour of larotrectinib compared with chemotherapy,” he continued.

 

In the weighted analysis, larotrectinib was favoured over the control regimen in terms of time to subsequent systemic therapy (HR, 0.09), time to mutilating surgery (HR, 0.45), and time to complete surgical resection (HR, 0.42).

 

Median time to radiation therapy was not reached in either arm owing to the low number of events.

 

There was a trend for an overall survival benefit with larotrectinib vs the control regimen (HR, 0.22).

 

Safety-wise, none discontinued larotrectinib owing to treatment-emergent adverse events.

 

IFS is a very rare tumour (represents <1 percent of all childhood cancers) but is the most frequent soft tissue sarcoma type in infants <1 year. “This tumour occurs at a median age of 2.6 months, which means that we are treating very young patients. The late effect of drugs and other therapeutic strategies … should be taken into consideration,” said Orbach.

 

“The cornerstone of treatment is still surgery but in half of the patients, the tumour is unresectable [hence the need for] preoperative cytoreductive treatment and local therapy, including conservative surgery,” he continued.

 

Conventional therapy for IFS involves treatment with vincristine-D/actinomycin (VA) with or without cyclophosphamide. VA reportedly yields a response rate of 68 percent and a 3-year OS rate of 94 percent. However, this is countered by weekly IV injections and acute side effects.

 

Conversely, larotrectinib has a higher response rate (90 percent) and 4-year OS (97 percent). Moreover, it is orally administered and has a favourable safety profile.

 

“This is the first study to provide comparative data on larotrectinib vs SoC in IFS patients … [Our] findings confirm the important role of larotrectinib in the overall treatment strategy of patients with IFS,” said Orbach.