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ESMO Sarcoma and Rare Cancers Congress

Image Credit: © Katsyarina – stock.adobe.com

Long-term treatment with nirogacestat (Ogsiveo) was linked with an improved objective response rate (ORR), further reduction in tumor size, and sustained quality-of-life benefits in patients with desmoid tumors, according to updated from the phase 3 DeFi (NCT03785964) presented at the 

2025 ESMO Sarcoma and Rare Cancers Congress

Patients in the intention-to-treat population (n = 70) had a median duration of nirogacestat exposure of 33.6 months (range, 0.3-61.8). An increased ORR was observed in those who received the agent for up to 4 years vs those who continued treatment for up to 1 year, at 45.7% (complete response [CR], 11.4%; partial response [PR], 34.3%) and 34.3% (CR, 4.3%; PR, 30.0%), respectively. Across years 3 and 4, additional CRs and PRs were reported in 3 patients each.

“These results show the long-term efficacy and safety of continuous use of nirogacestat with a median exposure of [33.6] months, extended from 20.6 months at the primary analysis,” lead study author Bernd Kasper, MD, PhD, of the Sarcoma Unit at the University of Heidelberg and Mannheim University Medical Center, Mannheim Cancer Center, in Germany, said during a presentation of the data.

 for the treatment of adult patients with progressing desmoid tumors who require systemic treatment.

 This regulatory decision was based on previously reported data from DeFi.

The global, multicenter, randomized, placebo-controlled trial enrolled adult patients with desmoid tumors progressing by at least 20% per RECIST 1.1 who were randomly assigned 1:1 between the nirogacestat and placebo arms.

 In double-blind portion of the study, patients received 150 mg of nirogacestat twice per day (n = 70) or placebo. During the open-label extension portion of the study, patients in the experimental arm continued twice-daily dosing with nirogacestat (n = 39), and eligible patients in the placebo arm were allowed to begin receiving nirogacestat at 150 mg twice per day.

The primary objective of DeFi was to evaluate the efficacy and safety of nirogacestat at years 1 to 4. In the landmark ORR analysis, investigators looked at patients randomly assigned to the nirogacestat arm in the double-blind portion of the study prior to the data cutoff date of December 19, 2024.

The primary end points of the landmark analysis were tumor response and durability per RECIST 1.1; patient-reported outcomes (PROs); and safety.

Additional findings demonstrated that among evaluable patients in the nirogacestat arm (n = 66), the median best change in target tumor size was –32.3% (range, –100% to 6%) with at least 1 year of treatment (n = 46), –42.5% (range, –100% to 2%) with at least 2 years of treatment (n = 40), –51.3% (range, –100% to 2%) with at least 3 years (n = 33), and –75.8% (range, –100% to 2%) with at least 4 years (n = 15).

Notably, PRO gains were sustained in patients who received nirogacestat. The least squares (LS) mean change from baseline ranged from –1.26 to –1.86 for BPI-SF average worst pain intensity score; –0.84 to –1.26 for DTSS total symptom score; and –0.41 to –0.69 for DTIS physical functioning. LS mean change from baseline ranged from –0.60 to 7.96 for EORTC QLQ-C30 GHS/QoL score; 0.88 to 7.83 for EORTC QLQ-C30 physical functioning score; and 8.45 to 14.18 for EORTC QLQ-C30 role functioning score.

Regarding safety (n = 69), most treatment-emergent adverse effects (TEAEs) were grade 1 or 2, and the incidence and severity of common TEAEs decreased after year 1. The most frequently reported TEAEs consisted of diarrhea, nausea, ovarian toxicity, fatigue, hypophosphatemia, and headache.

Data regarding ovarian toxicity were consistent with findings from the study’s primary analysis. Three patients experienced an additional instance of ovarian toxicity following a previously reported TEAE, and 1 patient experienced first-time ovarian toxicity.

Between years 2 and 3, TEAEs led to dose reductions in 5 patients; no patients required dose reductions after year 3.

Kasper B, Ratan R, Alcindo T, et al. Long-term nirogacestat treatment in adult patients with desmoid tumors: Updated efficacy and safety from the phase III DeFi trial. 

. 2025;10(suppl 3):104381. doi:10.1016/j.esmoop.2025.104381

FDA approves nirogacestat for desmoid tumors. FDA. November 27, 2023. Accessed March 26, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nirogacestat-desmoid-tumors

Long-term nirogacestat treatment in desmoid tumor patients demonstrated improved objective response rates, tumor size reduction, and sustained quality-of-life benefits. The phase 3 DeFi trial showed increased efficacy with prolonged treatment, with a median exposure of 33.6 months. The trial's primary endpoints included tumor response, durability, patient-reported outcomes, and safety. Most treatment-emergent adverse effects were mild, with decreased incidence and severity over time. The FDA approved nirogacestat in 2023 for adult patients with progressing desmoid tumors, based on earlier DeFi trial data.

Nirogacestat sustained long-term efficacy with acceptable safety in patients with desmoid tumors treated in the phase 3 DeFi trial.

Nirogacestat Provides Long-Term Benefits in Desmoid Tumors

Elective discontinuation following response to larotrectinib (Vitrakvi) was shown to be safe and feasible in pediatric patients with 

fusion–positive infantile fibrosarcoma or other soft tissue sarcomas, according to data from the phase 1/2 SCOUT trial (NCT02637687) that were presented at the 

2025 ESMO Sarcoma and Rare Cancers Annual Congress

At a data cutoff of July 20, 2023, and median follow-up of 41 months, all 47 patients were alive. The median time to discontinuation was 15 months (range, 3-65). Thirty-four percent of patients (n = 16) who discontinued larotrectinib had subsequent progression. The median time from discontinuation to progression was 3 months (range, 1-35).

“Larotrectinib demonstrated robust, durable responses and favorable safety in pediatric patients with 

fusion sarcomas who had a drug holiday. These data suggest that patients with completely resected localized tumors can discontinue larotrectinib” Claudia Blattmann, MD, lead study author and medical director of the Department of Oncology, Hematology, and Immunology at Olgahospital in Stuggart, Germany, and coauthors, said in the presentation.

 gene fusions are oncogenic drivers of several malignancies, including infantile fibrosarcoma, presenting in up to approximately 70% of cases and other pediatric sarcomas. In 2018, larotrectinib, the first-in-class, highly selective TRK inhibitor, 

received the second tissue-agnostic FDA approval in oncology

 for the treatment of adult and pediatric patients with solid tumors that have an 

The present study was performed to better understand outcomes in pediatric patients with 

 fusion–positive sarcomas who electively discontinued the agent while in response.

The trial enrolled pediatric patients up to 21 years of age with advanced solid tumors. Patients received a maximum dose of 100 mg/m

 of larotrectinib twice daily. Patients in the dose-escalation cohort received between 9.6 and 120 mg/m

 of larotrectinib twice daily based on target dosing calculation tables per protocol. All patients were actively followed for progression, and those who re-started larotrectinib due to progression were re-evaluated by investigators for response per RECIST 1.1.

The primary end points were time to discontinuation, time from discontinuation to progression, and time from progression to resumption of treatment. The secondary end point was safety.

Of the 99 pediatric patients who were enrolled, 47 patients with 

fusion–positive sarcoma were allowed to discontinue larotrectinib in the absence of on-treatment disease progression.

Baseline characteristics indicated that the median age was 0.9 years (range, 0-13). Most patients were male (53%), had an ECOG performance status of 0 (83%), and infantile fibrosarcoma (64%) as opposed to other soft tissue sarcomas (36%). Only 

 (64%) gene fusions were represented in the study population. The median number of prior lines of therapy was 1 (range, 0-3). Prior lines of therapy included surgery (28%), radiotherapy (2%), and systemic therapy (55%). The best response to prior systemic therapy included complete response (CR; 2%), partial response (PR; 9%), stable disease (SD; 28%), progressive disease (9%), or other (9%). Forty-five percent of patients did not receive prior systemic therapy.

By the data cutoff, 64% of patients with infantile fibrosarcoma and 36% with other soft tissue sarcomas discontinued larotrectinib and entered the wait-and-see period in the absence of on-treatment progression. Fifty-three percent of patients discontinued treatment after achieving CR, which included 10 surgical patients with pathological CR (pCR), 38% with PR, and 9% with SD. Forty-five percent of patients electively discontinued larotrectinib after surgery, which took place up to 1 week after discontinuation, and 55% did not undergo surgery.

Investigators also evaluated time to discontinuation and progression in the surgical (n = 21) and non-surgical (n = 26) subgroups, whose follow-up ranged from 36 months to 41 months.

Within the non-surgical population, the median time to discontinuation was 20 months (range, 11-65). Twelve patients progressed, and the median time from discontinuation to progression was not reached (NR; range, 1-59).

The surgical population was further stratified by best response before or at the time of stopping larotrectinib. Patients whose best response was pCR (n = 10) had a median time to discontinuation of 7 months (range, 5-22). Two patients progressed, and the median time from discontinuation to progression was NR (range, 0-76). For patients whose best response was either R0 (n = 1), R1 (n = 8), or R2 (n = 1) resection, the median times to discontinuation were 22 months (range, 22-22), 8 months (range, 4-26), and 6 months (range, 6-6), respectively. One patient each with R1 and R2 resection experienced disease progression, and the median times from discontinuation to progression were NR (range, 1-78) and 1 month (range, 1-1), respectively.

Additional results indicated that 4 patients who underwent surgery and 12 who did not experienced disease progression. The median time from discontinuation to progression was NR in both the surgical and non-surgical groups. Ten patients with infantile fibrosarcoma and 6 with other soft tissue sarcomas had disease progression. The median time from discontinuation to progression was also NR in both histologic groups.

Best response after progression and resumption of treatment was also evaluated. Of the 16 patients who discontinued larotrectinib and had subsequent progression, all resumed treatment with the agent. Eleven patients had response to re-treatment, including 5 CRs, 6 PRs, and 4 cases of SD. Response was undefined in 1 patient who had re-started treatment and then underwent surgery.

Within the non-surgical cohort (n = 26), 12 patients had progressed and resumed treatment. Best responses after re-treatment included 4 CRs, 4 PRs, 3 cases of SD, and 1 response that was undefined. Within the surgical cohort (n = 21), best responses after re-treatment were 1 CR and 1 PR in the pCR population (n = 10), 1 PR in the R1 population (n = 8), and 1 case of SD in the R2 population (n = 1).

Regarding safety, treatment-related adverse effects (TRAEs) were mostly grade 1 or 2. Grade 3/4 TRAEs occurred in 34% of patients, the most common of which was neutrophil count decrease (any grade, 29.8%; grade ≥3, 19.1%). Other TRAEs were vomiting (any grade, 10.6%; grade ≥3, 2.1%), cough (any grade, 4.3%), increased aspartate aminotransferase (any grade, 48.9%), increased alanine aminotransferase (any grade, 44.7%; grade ≥3, 2.1%), diarrhea (any grade, 10.6%), anemia (any grade, 21.3%), constipation (any grade, 14.9%), blood alkaline phosphatase increase (any grade, 19.1%; grade ≥3, 6.4%), leukocyte count decrease (any grade, 25.5%), weight increase (any grade, 14.9%; grade ≥3, 6.4%), nausea (any grade, 21.3%), headache (10.6%), urinary tract infection (any grade, 2.1%), dry skin (any grade, 2.1%), platelet count decrease (any grade, 10.6%), hypoglycemia (any grade, 2.1%), lymphocyte count decrease (any grade, 17%), and pain in extremity (any grade, 2.1%).

No patients discontinued larotrectinib because of a TRAE.

Disclosures: Blattman had nothing to report.

Blattmann C, Mascarenhas L, Orbach D, et al. Treatment discontinuation outcomes in paediatric patients with TRK fusion sarcomas treated with larotrectinib. 

. 2025;10(suppl 3):104376. doi:10.1016/j.esmoop.2025.104376

FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Updated December 14, 2018. Accessed March 27, 2025. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions

Pediatric patients with TRK fusion–positive sarcomas may be able to safely discontinue larotrectinib and resume treatment if needed without sacrificing response. 

Elective Discontinuation May Be Possible With Larotrectinib in TRK Fusion–Positive Sarcomas

Reduced Radiotherapy Margins in High-Grade 

Glioma | Sebastian Kaulitzki – stock.adobe.com

The use of reduced radiotherapy margins did not lead to differences in oncologic outcomes vs the use of conventional RTOG protocol–recommended margins in patients with newly diagnosed high-grade glioma (HGG), according to findings from a multicenter, randomized, open-label trial (IRCT20210215050367N1) that were presented at the 

Investigators observed no significant difference in recurrence patterns between study arms (

= .829), with in-field recurrences accounting for most recurrences in both the intervention (84%) and control (83.8%) groups. Marginal and out-field recurrences occurred infrequently (8% and 8%, respectively, in the interventional arm vs 9.2% and 6.9%, respectively, in the control arm).

Furthermore, the median progression-free survival (PFS) was 15.0 months (95% CI, 12.5-17.4) in the intervention group and 19.0 months (95% CI, 13.6-24.3) in the control group (

 = .121), supporting the noninferiority of the reduced-margin strategy. The mean PFS was 17.03 months (± 1; 95% CI, 15.05-19.01) in the intervention arm vs 19.48 months (±1.1; 95% CI, 17.16-21.81) in the control arm.

“The current standard of care [SOC] in the management of HGG is maximal surgical resection and postoperative concurrent chemoradiotherapy and maintenance chemotherapy up to 6 cycles,” Seyed Alireza Javadinia, MD, vice president for Research and Technology at Sabzevar University of Medical Sciences in Iran, explained in the presentation. “[This study showed that] a 2-phase radiotherapy approach with reduced margins can provide similar oncologic outcomes [compared with SOC] and minimize the dose to organs at risk. [However], high in-field recurrences in both groups show the need for more investigations for local treatments to enhance the efficacy of treatments.”

Historically, the phase 3 RTOG 0525 (NCT00304031) and RTOG 0825 (NCT00884741) trial protocols have advocated a 2-phase radiation approach, using a 2-cm clinical target volume (CTV) margin around peritumoral edema and a 2.5-cm CTV margin around the enhancing tumor. More recent ESTRO/ACROP guidelines established in 2023 proposed a CTV margin reduction to 1.5 cm, although consensus on the management of peritumoral edema remains lacking.

The multicenter, randomized, open-label, controlled trial evaluated the feasibility, safety, and efficacy of employing reduced radiotherapy margins compared with standard RTOG-defined margins in the adjuvant chemoradiation of adult patients with grade 3 or 4 newly diagnosed HGGs. Eligible patients underwent a 2-phase radiation protocol with concurrent and adjuvant temozolomide in accordance with established treatment strategies. The Stupp protocol was used for patients with grade IV gliomas and consisted of 6 cycles of temozolomide following radiotherapy. The phase 3 CATNON trial (NCT00626990) regimen was used for patients with grade 3 gliomas and consisted of temozolomide alone for 12 cycles post-radiotherapy.

Phase 1 of the trial delivered 46 Gy of radiation to the edema visible on FLAIR-weighted MRI with a 2-cm margin. In phase 2 of the trial, patients were randomly assigned to receive an additional 14 Gy of radiation directed to either of 2 treatment volumes: the surgical cavity and enhancing tumor residue on gadolinium-enhanced T1-weighted MRI with a 1-cm margin (investigational arm), or the same target with a 2-cm margin (control arm).

The primary end point was pattern of recurrence—classified as in-field, marginal, or out-field—based on the percentage of overlap between the 95% isodose line and the recurrent lesion. Specifically, in-field recurrences were defined by more than 80% overlap, marginal recurrences by 20% to 80% overlap, and out-field recurrences by less than 20% overlap. MRI imaging at the time of progression was registered to the original CT simulation images, and the enhancing component of recurrent disease was delineated to assess recurrence volume. Disease progression was defined using McDonald criteria.

A total of 258 adult patients with newly diagnosed grade 3 or 4 gliomas were enrolled. Baseline demographic and clinical characteristics were balanced between the intervention and control arms across most variables.

Patients had a mean age of 54.16 years (±11.27) in the intervention group and 56.64 years (±11.49) in the control group (

 = .959). The sex distribution was comparable, with males representing 61.5% and 60.0% of patients in the intervention and control arms, respectively (

= .8). Most patients had undergone subtotal resection (intervention arm, 76.2% vs control arm, 86.1%; 

 = .1), whereas fewer patients underwent gross total resection (14.1% vs 7.8%) or biopsy alone (9.9% vs 6.1%).

The trial included a higher proportion of patients with grade 4 gliomas in the intervention arm (81.2%) compared with the control group (68.7%); this difference reached statistical significance (

 mutation status was available in a subset of patients and was not statistically significantly different between the 2 groups (intervention arm, 20/36, 55.6%; control arm, 30/46, 65.2%; 

The type of radiation received was comparable across groups, with most patients receiving 3D conformal radiotherapy instead of intensity-modulated radiation therapy (88.8% vs 91.3%; 

 = .5). The duration of adjuvant chemotherapy was similar between the 2 groups, with a mean of 5.73 ± 3.31 months in the intervention arm and 5.19 ± 2.52 months in the control arm (

Regarding target volumes, the median gross target volume at 60 Gy (GTV60) was larger in the intervention group vs the control group (36.5 cm³ vs 23 cm³; 

= .3), and a similar trend was observed between the 2 respective arms for GTV46 (93.8 cm³ vs 51.4 cm³; 

 = .052). The mean CTV at 60 Gy (CTV60) was higher in the intervention group (140.33 ± 103.7 cm³ vs 124.12 ± 127.55 cm³; 

= .047); the CTV46 volumes were comparable between these respective arms (201.6 ± 157 cm³ vs 210.5 ± 171.3 cm³; 

Javadinia SA, Rabiei P, Anvari K, et al. A multicenter, randomized, open-label, controlled trial to compare recurrence pattern of reduced margins vs RTOG protocol in adjuvant chemoradiation of high-grade glioma. 

. 2025;10(suppl 3):104304. doi:10.1016/j.esmoop.2025.104304

A multicenter, randomized trial evaluated the efficacy of reduced radiotherapy margins versus conventional RTOG protocol margins in high-grade glioma (HGG) patients. Results showed no significant differences in recurrence patterns or progression-free survival (PFS) between the two groups, supporting the noninferiority of reduced margins. The study highlighted the need for further investigation into local treatments due to high in-field recurrences. The trial involved 258 patients, with balanced demographics and clinical characteristics, and utilized a 2-phase radiation protocol with concurrent and adjuvant temozolomide.

A randomized trial found no significant differences in recurrence or survival with smaller radiation margins vs standard RTOG protocols in patients with HGG.

Reduced Radiotherapy Margins Yield Outcomes Comparable With Standard Margins in HGG

Treatment with eribulin mesylate (Halaven) generated overall survival (OS) outcomes similar to those seen with trabectedin (Yondelis) treatment in patients with locally advanced or metastatic liposarcoma who had previously been treated with doxorubicin, according to findings from a real-world efficacy comparison, which were presented at the 

The study, which used real-world-data from the TriNetX platform, showed that the median OS with eribulin (n = 558) was 347 days, and the median OS with trabectedin (n = 558) was 401 days (post-propensity score matching HR, 0.955; 95% CI, 0.820-1.112; 

= .614). The survival probabilities at the end-of-time window were 0.00% and 3.41% in the trabectedin- and eribulin-treated populations, respectively.

“The median OS in both arms are near identical,” presenting author Jesús Rodríguez Pascual, MD, PhD, stated in the presentation. “We cannot find any difference in the treatment with crossover or without crossover for treatment.” 

Pascual is the head of service at the Instituto Oncológico Vithas in Madrid, Spain.

Eribulin and trabectedin are both standard-of-care therapies for patients with advanced liposarcoma who have previously received doxorubicin-based therapy. 

 in 2016 based on findings from the liposarcoma cohort (n = 143) of a phase 3 trial (NCT01327885), in which the agent elicited a median OS of 15.6 months (n = 71; 95% CI, 10.2-18.6)) vs 8.4 months (95% CI, 5.2-10.1) with dacarbazine (n = 72; HR, 0.51; 95% CI, 0.35-0.75).

 Furthermore, the median progression-free survival (PFS) in these respective arms was 2.9 months (95% CI, 2.6-4.8) vs 1.7 months (95% CI, 1.4-2.6; HR, 0.52 [95% CI, 0.35-0.78]).

 in 2015 for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma based on findings from the phase 3 ET743-SAR-3007 trial (NCT01343277), in which patients with soft tissue sarcoma who received trabectedin (n = 345) achieved a median OS of 13.7 months vs 13.1 months among those who received dacarbazine (n = 173; HR, 0.93; 95% CI, 0.75-1.15; 

 The median PFS in these respective populations was 4.2 months (95% CI, 3.0-4.8) vs 1.5 months (95% CI, 1.5-2.6; HR, 0.55 [95% CI, 0.44-0.70; 

Currently, no head-to-head studies have compared eribulin vs trabectedin in this patient population.

“Advanced liposarcoma is an infrequent disease,” Pascual noted. “We focused on real-world data and used it to help to clarify the importance of eribulin and trabectedin in this scenario.”

TriNetX is a global collaborative network platform that uses anonymized, aggregate clinical data from 140 health care organizations.

This study included patients with advanced liposarcoma who were previously treated with doxorubicin-based therapy in the neoadjuvant, adjuvant, or palliative settings. Patients were not included if they had received crossover therapy with trabectedin after eribulin or vice versa. Investigators used propensity score matching to balance controls based on age, race, and gender.

Overall, 1828 patients from 128 health care organizations in the TriNetX platform were identified. In total, 1240 patients had received treatment with trabectedin, and 558 had been treated with eribulin. After propensity score matching, this study included 558 patients who had received trabectedin and 558 patients who had received eribulin.

“To date, this is the largest face-to-face comparison between these 2 therapeutic options. We are assured that focusing on real-world data can help to explore unanswered questions in the treatment of [patients with] advanced sarcoma,” Pascual concluded.

Pascual reported no conflicts of interest.

Pascual JR, Ugidos L, Rodriguez-Castaño JD, et al. Eribulin (E) versus trabectedin (T) therapy in patients with advanced liposarcoma: efficacy comparison using real-world data evidence from TriNetX platform. 

. 2025;10(suppl 3):104378. doi:10.1016/j.esmoop.2025.104378

FDA approves first drug to show survival benefit in liposarcoma. FDA. January 28, 2016. Accessed March 24, 2025. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-show-survival-benefit-liposarcoma

Halaven. Prescribing information. Eisai Inc. Updated September 2022. Accessed March 24, 2025. 

https://www.halaven.com/hcp/-/media/Files/Halaven/HALAVEN-Full-Prescribing-Information.pdf?&hash=4292bfe6-3c3f-4716-8f44-e2f2949229c8

U.S. FDA approves Yondelis (trabectedin) for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma, two common subtypes of soft tissue sarcoma. News release. Janssen Biotech, Inc. October 23, 2015. Accessed March 24, 2025. 

https://www.jnj.com/media-center/press-releases/us-fda-approves-yondelis-trabectedin-for-the-treatment-of-patients-with-unresectable-or-metastatic-liposarcoma-or-leiomyosarcoma-two-common-subtypes-of-soft-tissue-sarcoma

A real-world efficacy comparison presented at the 2025 ESMO Sarcoma and Rare Cancers Annual Congress revealed that eribulin mesylate and trabectedin produced similar overall survival outcomes in patients with advanced liposarcoma previously treated with doxorubicin. The study utilized data from the TriNetX platform, showing median overall survival of 347 days for eribulin and 401 days for trabectedin. This research, the largest direct comparison of these therapies, underscores the value of real-world data in addressing treatment questions for advanced sarcoma.

A real-world study showed OS outcomes with eribulin similar to those with trabectedin in doxorubicin-pretreated patients with advanced liposarcoma.

ESMO Sarcoma and Rare Cancers Congress | Conference

Nirogacestat Provides Long-Term Benefits in Desmoid Tumors

Elective Discontinuation May Be Possible With Larotrectinib in TRK Fusion–Positive Sarcomas

Reduced Radiotherapy Margins Yield Outcomes Comparable With Standard Margins in HGG

Eribulin and Trabectedin Yield Comparable Real-World OS Outcomes in Advanced Liposarcoma