Larotrectinib for Newly Diagnosed Infantile Fibrosarcoma and Other Pediatric NTRK Fusion-Positive Solid Tumors (Children’s Oncology Group ADVL1823)

Abstract

Purpose:

The TRK inhibitor larotrectinib is FDA-approved for NTRK fusion-positive solid tumors that lack a satisfactory alternative or have progressed following treatment, but has not been systematically studied as a frontline therapy with a defined duration of treatment. ADVL1823 evaluated larotrectinib in patients with newly diagnosed NTRK fusion-positive solid tumors with response-adapted duration of therapy and local control.

Methods:

Patients received larotrectinib twice daily in 28-day cycles for a pre-defined duration of treatment, ranging from 6–26 cycles depending on response to therapy and surgical resectability. The primary end point was the objective response rate (ORR) within 6 cycles in patients with infantile fibrosarcoma (IFS); patients with other histologic diagnoses were analyzed in a separate cohort. Secondary objectives included event-free (EFS) and overall survival (OS).

Results:

33 patients were enrolled: 18 with IFS and 15 with other solid tumors. The ORR within 6 cycles was 94% (17/18, 95% Adjusted CI: 72.7%-98.6%) among children with IFS and 60% (9/15, 95% CI: 32.3%-83.7%) among children with other solid tumors. 6% (2/33, 95% CI: 0.7%-22.2%) patients developed progressive disease while on therapy. 2-year EFS and OS among these groups were 82.2% (95% CI: 54.3%-93.9%) / 93.8% (95% CI: 63.2%-99.1%) for IFS and 80% (95% CI: 50.0%-93.1%) / 93.3% (95% CI: 61.3%-99.0%) for other solid tumors, respectively. Patients undergoing surgical resection of their tumor had prolonged EFS with only one of 16 such patients experiencing disease progression. Four of 33 patients had dose limiting toxicities.

Conclusion:

Larotrectinib is highly active in patients with newly diagnosed NTRK fusion-positive solid tumors. Larotrectinib should be a frontline option for patients with IFS and other NTRK fusion-positive solid tumors. Local control with surgical resection remains important in the treatment of patients with IFS.

Introduction

Infantile fibrosarcoma (IFS) is a rare soft tissue sarcoma characterized by nearly universal kinase activating alterations including ETV6::NTRK3 fusions in ~85% of cases.^1–10 Clinically, IFS almost always presents as a localized tumor, although rare metastases have been described.^11,12 While surgical resection is usually curative, infants frequently present with rapidly growing unresectable tumors requiring systemic therapy.^13,14

Traditionally, patients with IFS have been treated with vincristine and actinomycin-based chemotherapy.¹⁵ In the largest prospective study to date, 27 children with unresectable IFS were reported to have an objective response (>33% reduction in tumor volume) rate of 62.9%.¹³ While the majority achieved disease control, there was still a significant burden of therapy, including a patient who died of toxicity, 6 who received alkylator based therapy, 3 who developed venocclusive disease (VOD), 2 who underwent limb amputation, and 1 who underwent exenteration.¹³

Beyond IFS, NTRK gene fusions occur across a range of other pediatric cancers, including gliomas, thyroid cancer, congenital mesoblastic nephroma (CMN), and the recently designated NTRK-rearranged spindle cell neoplasm (WHO 2020).^16,17 To date, published treatment and outcome data for the subset of pediatric patients with other diagnoses harboring NTRK fusions is very limited, outside of thyroid cancer and CMN.^18,19

Larotrectinib is a highly selective TRK inhibitor and has been approved by the FDA for the treatment of patients with NTRK fusion-positive solid tumors that lack satisfactory alternative treatments or have progressed following treatment. This approval was based on a 75% response rate across children and adults with a wide range of NTRK fusion-positive cancers.^20,21 The majority of patients enrolled on these trials had relapsed or refractory disease, and frontline use of larotrectinib has not been systematically evaluated.²² Thus, ADVL1823 was designed to evaluate larotrectinib given for a defined treatment duration in newly diagnosed patients with NTRK fusion-positive tumors in two cohorts: IFS and other solid tumors.

Methods

Study Design and Eligibility

ADVL1823 was reviewed by the NCI Pediatric Central Institutional Review Board and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from patient/parents/guardians, and assent was also obtained from the patient where appropriate. Patients ≤30 years of age with any newly diagnosed NTRK fusion-positive solid tumor (except high-grade glioma) were eligible for enrollment into one of two cohorts: Cohort A for IFS, and Cohort B for any other solid tumor. Cohort C was an exploratory cohort for NTRK fusion-positive relapsed or refractory leukemia, but no patients were enrolled.

NTRK fusions were identified locally in CLIA/CAP certified laboratories by break-apart FISH, RT-PCR, or NGS. Patients with IFS or CMN were allowed to enroll with FISH confirmation of ETV6 rearrangement; all other patients required confirmation of the involved NTRK gene. Retrospective confirmation of fusions was performed with a RNA-based NGS assay in a central CLIA laboratory, as previously described.²³ Patients were required to have measurable disease by RECIST v1.1 or modified RANO criteria that was not surgically resectable, Lansky or Karnofsky performance score of ≥ 50%, and adequate organ function. No prior anti-cancer therapy, other than surgical resection of the tumor, was permitted.

Larotrectinib was given orally, twice daily at the FDA approved dose of 100mg/m²/dose with a maximum of 100 mg/dose continuously in 28-day cycles. Patients received drug for a minimum of 6 cycles provided there was no evidence of disease progression (Supplemental Figure 1). After a minimum of 6 cycles, patients who achieved a complete response (CR) were treated for an additional 6 cycles after achieving CR or 12 total cycles, whichever was longer, and then entered follow-up. Patients with localized tumors and partial response (PR) or stable disease (SD) whose tumors became resectable underwent on-study surgical resection. Following resection, those with negative margins (or gross total resection in the case of IFS/CMN) entered follow-up. Patients with incomplete resections were permitted to resume protocol therapy. Remaining patients received a total of 26 cycles of therapy and then entered follow-up.

Measurement of Response

Any eligible patient who received at least one dose of protocol therapy was evaluable for response. Tumor disease evaluations were obtained after cycles 2, 4, 6, 9, 12, 16, 20 and 24 for patients who continued protocol therapy. Patients completing planned therapy had disease evaluations 3, 6, 12, 18, 24, 30, 36, and 48 months after discontinuation of larotrectinib in the absence of PD. For documentation of objective response, confirmatory scans were required. RECIST version 1.1 was used to determine response and progression for extracranial solid tumors and modified RANO criteria were used for CNS tumors.^24,25 Investigator assessed response was used to guide treatment and is reported for time-to-event endpoints; central review was performed retrospectively for imaging while on therapy and is reported here for the primary objective and objective response rates (ORR).

Adverse Events and Dose Modifications

The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used for adverse event reporting. All patients who received at least one dose of protocol therapy were evaluable for toxicity. Treatment could be withheld for DLTs for up to 21 days. If the DLT resolved to eligibility parameters within 21 days of discontinuing therapy, the patient resumed larotrectinib at a reduced dose. Up to three dose reductions were permitted by protocol.

Statistical Considerations

The study’s primary end point was ORR in patients with IFS (Cohort A). The study used a Simon’s minimax two-stage design with 9 patients in the first stage and 12 patients in the second stage. The ORR was compared against a null benchmark value of 60% (chosen based on the response rate to chemotherapy in IFS). With this design (alpha=9%), the power was 90% to detect an improvement in response rate to 85%. Accrual to cohort B was planned to be simultaneous with that to Cohort A, and the above two-stage design would be applied if any single histology accrued at least 9 patients.

Event-free (EFS) and overall survival (OS) were secondary clinical endpoints and calculated using the Kaplan-Meier method. EFS was defined as the time from enrollment to disease progression, secondary malignancy, or death from any cause. Patients without an event were censored at the last reported disease assessment. As an exploratory analysis, a landmark EFS analysis was conducted starting from the time of treatment discontinuation stratified by surgical status. OS was defined as the time from enrollment to death from any cause. Patients who remained alive were censored at last follow-up.

Confidence intervals for proportions were adjusted for the two-stage design where noted.²⁶

All statistical analyses were done in SAS (version 9.4).

Results

Patients

Between October 2019 and July 2022, 33 patients enrolled; 18 to cohort A with IFS and 15 to cohort B with other NTRK fusion-positive solid tumors: 7 with various mesenchymal soft tissue tumors, here grouped as NTRK-rearranged spindle cell tumors, 3 each with CMN and low-grade glioma (LGG), and 2 with inflammatory myofibroblastic tumor (IMT). Accrual was halted early after there were 16 confirmed responders with IFS, meeting the pre-specified efficacy threshold.

The median age at enrollment was 8 months (2 months in cohort A and 9 years in cohort B; Table 1). All patients in cohort A and 13 in cohort B had localized unresectable disease, while 2 in cohort B had metastatic disease. The most common NTRK fusions were ETV6::NTRK3 in 21 tumors and TPM3::NTRK1 in 3. Fusions were locally identified by NGS (n=19, 58%), FISH (n=11, 33%), and RT-PCR (n=3, 9%). Tissue was available for central confirmation of fusion status for 28/33 patients, and all had the locally reported fusion confirmed.

Table 1:

Patient demographics

Characteristic	Cohort A (n=18)	Cohort B (n=15)	All patients (n=33)
Age, median	2 mo	9 yr	8 mo
range	<1 mo - 4.6 yr	4 mo – 20 yr	<1 mo - 20 yr
Sex, female (%)	6 (33%)	8 (53%)	14 (42%)
Diagnosis
IFS, n (%)	18 (100%)	0	18 (55%)
NTRK-rearranged spindle cell tumor*	0	7 (47%)	7 (21%)
CMN	0	3 (20%)	3 (9%)
LGG	0	3 (20%)	3 (9%)
IMT	0	2 (13%)	2 (6%)
Localized, n (%)	18 (100%)	13 (87%)	31 (94%)
Metastatic, n (%)	0	2 (13%)	2 (6%)
NTRK fusion, n (%)
ETV6::NTRK3	16 (89%)	5 (33%)	21 (64%)
TMP3::NTRK1	1 (6%)	2 (13%)	3 (9%)
AFAP1::NTRK2	0	2 (13%)	2 (6%)
DCTN1::NTRK1	1 (6%)	1 (7%)	2 (6%)
LMNA::NTRK1	0	1 (7%)	1 (3%)
BCAN::NTRK1	0	1 (7%)	1 (3%)
TPR::NTRK1	0	1 (7%)	1 (3%)
VIM::NTRK3	0	1 (7%)	1 (3%)
EML4::NTRK3	0	1 (7%)	1 (3%)
RBPMS::NTRK3	0	1 (7%)	1 (3%)
Fusion assay, n (%)
NGS	7 (39%)	12 (80%)	19 (58%)
FISH	8 (44%)	3 (20%)	11 (33%)
RT-PCR	3 (17%)	0	3 (9%)

^*Includes tumors reported as sarcoma, not otherwise specified; malignant tumor, spindle cell type; spindle cell sarcoma; and malignant mesenchymoma. IFS = Infantile fibrosarcoma, CMN = congenital mesoblastic nephroma, LGG = low-grade glioma, IMT = inflammatory myofibroblastic tumor

As of the March 31, 2024, data cutoff, 88% (29/33) of patients remained on study while 4 were off study due to withdrawal of consent in follow-up (n=2) or death (n=2). No patients remained on treatment. 16 patients discontinued treatment at the time of complete surgical resection, 14 following completion of the planned duration of therapy, 2 for on treatment disease progression, and one for physician discretion after 21 cycles of therapy (Figure 1 and Supplemental Figure 1).

Figure 1:

CONSORT diagram

Response

In cohort A, the ORR within 6 cycles was 94% (17/18, 95% Adjusted CI: 72.7%-98.6%; 1 CR, 16 PR, Figure 2). The only patient without a confirmed objective response demonstrated 47% tumor reduction after cycle 2, but no confirmatory scan was obtained within the first 6 cycles and thus was considered a non-responder according to the study design; a PR was subsequently confirmed in cycle 7. Four patients with a PR during cycles 1–6 were confirmed to have CR after cycle 6, for an overall response rate of 100% (18/18, 95% Adjusted one-sided CI: 84.7%-100%; 5 CR, 13 PR) during treatment. Figure 3 shows representative imaging in a patient with IFS.

Figure 2:

Waterfall plot: Best percent change in the sum of the maximal tumor diameters by central radiology review. Patient with 0% change had LGG with an NTRK2 gene fusion. Overall best response (OBR) indicates best confirmed response within the first 6 cycles. IFS = Infantile Fibrosarcoma; LGG = Low-Grade Glioma; Spindle = NTRK-Rearranged Spindle Cell Neoplasm; IMT = Inflammatory Myofibroblastic Tumor; CMN = Congenital Mesoblastic Nephroma

Figure 3:

Representative imaging in a patient with infantile fibrosarcoma. Axial fat-suppressed T2 (upper row) and sagittal post-gadolinium enhanced fat-suppressed T1-weighed images were obtained at Baseline and Reporting Periods 2 and 8. At baseline the * indicates the large enhancing soft tissue mass in the lateral compartment of the foot and ankle. Residual enhancement and soft tissue changes are still evident after 2 cycle of therapy (RP 2, arrow) although the mass has decreased dramatically in size. At reporting period 8 no residual enhancement or soft tissue abnormalities are seen.

In cohort B, the ORR within 6 cycles was 60% (9/15, 95% CI: 32.3%-83.7%; 9 PR, 6 SD). Two patients with SD during the first 6 cycles were subsequently confirmed to have responses after cycle 6 for an overall response rate of 73% (11/15, 95% CI: 44.9%-92.2%; 1 CR, 10 PR, 4 SD) during treatment. Responses were observed in 71% (5/7) with NTRK-rearranged spindle cell tumors, 100% (3/3) with CMN, 33% (1/3) with LGG, and 100% (2/2) with IMT.

Across both cohorts, responses on therapy were seen in 88% (29/33, 95% CI: 71.8%-96.6%) of patients including 71% (5/7) with NTRK1 fusions (1 CR, 4 PR, 2 SD) and 96% (23/24) with NTRK3 fusions (5 CR, 18 PR, 1 SD). Both patients with NTRK2 fusions had LGG and 1 of 2 had a PR. Responses were rapid with 76% (25/33) of patients having a PR at the first on therapy disease assessment (Figure 4 and Supplemental Figure 2).

Figure 4:

Swimmer plot. On Treatment = On treatment without objective response. IFS = Infantile Fibrosarcoma, LGG = Low-Grade Glioma, Spindle = NTRK-Rearranged Spindle Cell Neoplasm, IMT = Inflammatory Myofibroblastic Tumor, CMN = Congenital Mesoblastic Nephroma

Given the evolution of WHO classification of these tumors, we also analyzed the patients with NTRK-rearranged spindle cell tumors as a group (including all IFS and 7 NTRK-rearranged spindle cell tumors). Among this group, the ORR was 92% (23/25; 95% CI: 74.0%-99.0%; 6 CR, 17 PR, 2 SD). 48% (12/25) of patients underwent on study surgical resection, all but one were reported to have complete resections and discontinued larotrectinib at the time of surgery. All remain event-free after a median of 18 (range 0–36) months of follow-up after discontinuation of larotrectinib.

Survival outcomes

In cohort A, the 2-year EFS and OS were 82.2% (95% CI: 54.3–93.9%) / 93.8% (95% CI: 63.2%-99.1%), and in cohort B these were 80% (95% CI: 50.0%-93.1%) / 93.3% (95% CI: 61.3%-99.0%), respectively (Figure 5). Only 6% (2/33, 95% CI: 0.7%-22.2%) of patients experienced disease progression at any point while on larotrectinib, a four-year-old with TPM3::NTRK1 fusion IFS and a one-year-old with ETV6::NTRK3 fusion CMN (Figure 4). Both patients eventually died of their disease; no other deaths occurred.

Figure 5:

Event free survival by cohort (A) and histologic diagnosis (B). Event free survival after treatment discontinuation in patients treated with or without surgery (C). Overall survival by cohort (D) and histologic diagnosis (E). CMN = Congenital Mesoblastic Nephroma; IFS = Infantile Fibrosarcoma; IMT = Inflammatory Myofibroblastic Tumor; LGG = Low-Grade Glioma; Spindle = NTRK-Rearranged Spindle Cell Neoplasm.

Among patients who discontinued therapy in the absence of disease progression, the EFS from end of therapy was higher among patients who underwent surgical resection of their tumor (p=0.002, Figure 5C). In cohort A, 47% (8/17) underwent resection of an initially unresectable tumor after a median of 7 (range 7–11) cycles of therapy and 53% (9/17) completed therapy without surgical resection (including 7 completing therapy with an investigator assessed response of CR and 2 with PR, Figure 4). Following surgical resection, no patient experienced disease progression with a median follow-up of 21 (range 0–30) months after treatment discontinuation. Among patients discontinuing therapy without surgery, 3 remain event-free with a median follow-up of 18 (range 12–18) months while 6 experienced disease progression at the primary site of disease, all within 4 months of larotrectinib discontinuation (Figure 4, and Response to Retreatment below).

In cohort B, 57% (8/14) of patients discontinuing therapy in the absence of disease progression underwent resection of an initially unresectable tumor after a median of 7 (range 7–10) cycles of therapy and 43% (6/14) completed therapy without surgical resection. Of the 6 patients completing therapy without surgery, 2 each had an investigator assessed response of CR, PR, or SD (Figure 4). With a median follow-up of 21 (range 0–36) months following surgical resection, only one of eight patients experienced disease progression (at the primary site) approximately six months after discontinuing larotrectinib. Among patients discontinuing therapy without surgery, 83% (5/6) remain event-free (Figure 4). However, the median follow-up of this group of patients is only 6 (range 0–30) months after treatment discontinuation.

Safety

11 patients experienced a treatment related CTCAE grade 3 or higher AE (Supplemental Table 1). The only grade 3 or higher treatment related AE occurring in more than 1 patient was neutropenia, occurring in 6. Four of the AEs (2 neutropenia, 1 AST elevation, and 1 weight loss) were dose limiting and resulted in dose interruption and reduction. All patients resumed treatment and no patients discontinued therapy for an adverse event.

All subjects who developed a grade 3 or higher treatment related AE had the first occurrence of that AE within the first 4 cycles of therapy, with the exception of 1 subject with weight gain that became grade 3 in cycle 8. No other grade 3 or higher weight gain was reported. Other cumulative toxicity was not observed over a median of 12 (range 4–26) cycles of treatment.

Surgical Outcomes

Among the 16 patients without prior disease progression undergoing on study surgical resection after a median of 7 (range 7–12) cycles of therapy, 15 (8 in cohort A and 7 cohort B) were reported to have a negative margin (R0) resection, and one in cohort B had a marginal (R1) resection. All patients with R0 resections discontinued larotrectinib at the time of surgery, while the patient with a R1 resection of a NTRK-rearranged spindle cell tumor resumed therapy and completed 26 cycles per protocol. One patient was reported to have neurological impairment after surgery. No other surgical morbidity or wound complications were reported.

Sufficient tissue from surgical resection to assess margin status centrally was submitted from 6 patients undergoing on-study surgical resection. Contrary to institutional review, by central review, all had treated tumor bed at the cut surface, although 5 of 6 had no viable or TRK IHC positive tumor cells identified. Despite these potential marginal (R1) resections, all 6 patients remain event-free without further therapy after a median of 21 (range 12–30) months of follow-up after discontinuation of larotrectinib.

Re-response to treatment

All 8 patients who progressed after completing the prescribed duration of larotrectinib were re-treated with commercial larotrectinib at their physician’s discretion while in follow-up. Among these 8 patients, response to retreatment was reported for 6 with 1 patient not evaluable as they underwent surgery at recurrence prior to larotrectinib treatment and 1 without follow-up imaging data reported. 83% (5/6 evaluable patients) experienced sufficient tumor shrinkage on retreatment to be considered an objective response by RECIST (3 CR, 2 PR, 1 SD). No patient who progressed off treatment was reported to require subsequent therapy other than larotrectinib and/or surgical resection and all remain alive and in follow-up.

Discussion

On ADVL1823, larotrectinib demonstrated universal activity in patients with newly diagnosed IFS. The 100% ORR in IFS and rapidity of response compare favorably to the 62.9% response rate to vincristine-actinomycin chemotherapy reported by EPSSG.¹³ Further, this therapy was well tolerated with low rates of grade 3 or higher adverse events, primarily laboratory abnormalities, all of which were reversable, and cumulative toxicity other than weight gain was not observed. While vincristine-actinomycin chemotherapy is not typically associated with long term toxicity, it is notable that the risk may be higher in infants, including a risk of VOD.¹³ As an oral drug, larotrectinib does not require placement of central venous access. Thus, the favorable efficacy and toxicity profile observed here establish larotrectinib as a preferred frontline treatment for children with IFS and related NTRK-rearranged spindle cell tumors. Notably, the only patient with an NTRK-rearranged spindle cell tumor who required therapy other than larotrectinib or surgery was the patient with IFS who progressed on treatment. Consistent with this data, a recent observational study demonstrated prolonged time to medical treatment failure in patients with IFS treated with larotrectinib vs historical control chemotherapy.²⁷

Our study continues to demonstrate the importance of local control for IFS, as the majority of patients discontinuing therapy without local control experienced disease progression off treatment. Most patients with IFS not undergoing surgical resection were considered to have a complete response to therapy by the treating investigator. The minimum 6 cycle duration of therapy on this study was chosen to allow time to assess response by RECIST. Newly diagnosed patients with IFS who are able to undergo upfront gross total resection of their tumor have a low risk of recurrence without any systemic therapy.^13,14 Similarly, all patients with IFS on this study whose tumors became resectable remain in remission off therapy. Our work adds to prior experience from the first-in-child SCOUT larotrectinib trial demonstrating ability of neoadjuvant larotrectinib to facilitate local control in these tumors.²⁸ Thus, in practice, it may be reasonable to consider a shorter duration of treatment if the tumor becomes resectable without morbidity. Our data, along with the EPSSG data, suggest that a marginal resection involving treated tumor bed is still associated with durable response without subsequent therapy.

Nonetheless, this study also identifies a subset of patients with NTRK-rearranged spindle cell tumors, including IFS, who maintain durable remissions following treatment with larotrectinib without local control. It will be important to continue to evaluate biomarkers to attempt to prospectively identify these patients. Ongoing studies on this protocol include ctDNA and imaging analyses, noting that some patients classified as prolonged PR have subtle imaging findings without biopsy confirmation of actual residual disease. Future work including deep molecular characterization (whole exome, whole genome, and transcriptome sequencing as well as methylation profiling) will be important. Similarly, evaluation of post-treatment specimens to identify the molecular mechanisms of on therapy resistance and ctDNA to attempt to prospectively identify the rare patients who will develop resistance are needed.

As re-response to larotrectinib is common among patients who progress after treatment discontinuation, it is reasonable to consider a treatment holiday/wait-and-see approach for patients whose tumors remain unresectable or for whom resection remains morbid. The optimal duration of therapy for such patients remains to be defined. The three cohort A subjects who maintained their response off treatment on this study were treated for 12–14 cycles, while those six who progressed off treatment were treated for a median of 26 (range 12–26) cycles. While patient numbers are limited, this suggests that treatment duration alone is insufficient to predict relapse.

This study was the first histology-agnostic frontline therapeutic study conducted within the Children’s Oncology Group and demonstrated the feasibility of enrollment of this very rare molecularly defined cohort, with the enrollment rate exceeding expectation. Perfect concordance between local and confirmatory central molecular testing demonstrates that selection of patients based on local testing is a viable approach.

Limitations of this study include the small patient number given the rarity of these tumors and the need for longer term follow-up data to confirm the durability of response and to evaluate for late toxicity. ADVL1823 continues to follow patients for 5 years from study entry and longer-term data will be reported in the future. Parent reports of cognitive, adaptive, and behavioral functioning are being conducted on this study for which the data is not yet mature. Central review of pathology is ongoing given the evolving diagnostic classification of NTRK-rearranged spindle cell neoplasms and will be reported separately. It is likely that using current pathologic definitions, there will be some reclassification of diagnoses among patients enrolled on study. However, the very high level of activity of larotrectinib across the range of histologies comprising NTRK-rearranged spindle cell neoplasms, including IFS, suggests that these tumors can be treated similarly, so this reclassification is unlikely to impact the conclusions of this study.

In conclusion, larotrectinib is highly active and well tolerated in patients with newly diagnosed NTRK-rearranged spindle cell tumors, including IFS. Larotrectinib should be the preferred frontline treatment option with a goal of facilitating a non-morbid surgical resection in patients with localized tumors.

Context Summary:

Key Objective:

Is larotrectinib effective as frontline treatment of pediatric NTRK fusion-positive solid tumors, including infantile fibrosarcoma, when administered for a defined treatment duration with local control?

Knowledge generated:

Larotrectinib was highly active in the frontline setting with 94% of children with infantile fibrosarcoma and 60% of children with other solid tumors demonstrating a confirmed objective response within 6 cycles of therapy. Patients undergoing surgical resection of their tumor had prolonged EFS even after discontinuing treatment with only one of 16 such patients experiencing disease progression. A subset of patients who maintained remission off treatment without local control was identified.

Relevance (written by Smita Bhatia):

This study provides a histology-agnostic frontline therapeutic approach based on molecular testing where the local testing was a viable option, providing evidence for a frontline therapeutic option for patients with NTRK fusion positive solid tumors.