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PARIS -- Progression-free survival (PFS) was significantly prolonged in patients with progressing desmoid tumors treated with an investigational gamma secretase inhibitor in a phase III trial.

In the international study of more than 140 patients, risk for disease progression or death was reduced by 71% in the group randomized to nirogacestat, with a median PFS not reached versus 15.1 months in the group assigned to placebo (HR 0.29, 95% CI 0.15-0.55, P<0.001), according to findings presented here by Bernd Kasper, MD, PhD, of Universitätsmedizin Mannheim in Germany.

"Nirogacestat demonstrated rapid, sustained, and statistically significant improvements in all primary and secondary efficacy endpoints," he said at the European Society for Medical Oncology (ESMO) annual congress. He added that the gamma secretase inhibitor was well tolerated and has "the potential to become the standard of care" for patients requiring systemic therapy.

There's a "clear mechanistic rationale" for using nirogacestat in this disease setting, said Kasper, as desmoid tumors highly express Notch, which can be blocked by gamma secretase inhibitors.

Objective response rate was significantly higher with nirogacestat (41% vs 8% with placebo, P<0.001), and five patients (7%) had complete responses with the oral drug versus none with placebo. Median time to response was twice as fast with nirogacestat as well (5.6 vs 11.1 months).

Desmoid tumors are rare, locally aggressive, invasive soft-tissue cancers that are challenging to manage due to their variable presentation and unpredictable clinical course, along with the lack of FDA-approved therapies, explained Kasper.

Depending on the presentation, individualized strategies for tumor control may include surgery, radiotherapy, or medical treatment, and active surveillance or watchful waiting can be acceptable options for indolent cases. Desmoid tumors rarely metastasize, and spontaneous regressions have been reported.

But tumor control is not the only goal for patients with desmoid tumors, said Kasper. "It's even more important to improve the symptom burden."

In DeFi, treatment with nirogacestat significantly reduced pain and disease symptom severity, and improved physical functioning and quality of life, he said. "These improvements occurred very early and were sustained through the whole trial," said Kasper, who noted that about 40% of the trial participants had uncontrolled pain at baseline.

"This improvement [in pain] is probably the most significant observation of this clinical trial, even though this was a secondary objective," said ESMO discussant Jean-Yves Blay, MD, PhD, of the Comprehensive Cancer Centre of Lyon in France.

For the primary endpoint of PFS, all patient subgroups experienced significant benefit with nirogacestat, said Blay, including those with prior tyrosine kinase inhibitor (TKI) exposure. A 2018 placebo-controlled study in advanced or refractory desmoid tumors demonstrated a "major improvement" with oral TKI sorafenib (Nexavar), he noted.

"Not addressed in this trial is symptomatic benefit in non-progressing tumors," highlighted Blay. "Many desmoid tumors do not have progression according to RECIST. Whether they would benefit [with nirogacestat] is likely, but not demonstrated here."

DeFi (Desmoid/Fibromatosis) was a double-blind phase III trial that randomized 142 patients with progressing desmoid tumors at 37 sites in North America and Europe to 28-day cycles of either twice-daily nirogacestat (150 mg) or placebo. The primary endpoint was PFS, while secondary endpoints included objective response, symptom burden, physical and role function, and quality of life. Upon radiographic disease progression, all patients in the placebo arm were eligible for an open-label extension study of nirogacestat.

Participants were eligible if they had treatment-naive tumors not amenable to surgery, or if they were refractory or had recurrent disease following one prior line of therapy.

Patient-reported outcomes were recorded at cycle 10. For nirogacestat versus placebo, these included improvements in pain on the Brief Pain Inventory-short form (BPI-SF); in desmoid tumor-specific symptom severity (DTSS) on ; and in physical and role functioning, also on GODDESS (P<0.001 for all):

• BPI-SF: -1.5 difference
• DTSS: -1.6 difference
• Physical/role functioning: -0.8 difference

With nirogacestat, physical and role functioning were also significantly improved on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (P<0.001 for both), as were global quality-of-life scores (P=0.007).

Baseline characteristics were generally well balanced between the two arms, said Kasper. Median age was 34, and about two-thirds were women. Groups were stratified by intra-abdominal (25%) and extra-abdominal (75%) tumor site. Around 40% of patients in the two arms had multifocal disease, and among those analyzed, 79%-84% had CTNNB1 mutations and 21%-22% had APC mutations.

For prior therapies, 26% of patients in the study arm were treatment-naive versus 19% of those in the placebo arm. Median number of prior treatments among the participants was two. This included surgery in 44% and 61% of the nirogacestat and placebo arms, respectively, radiotherapy in 23% and 22%, and systemic therapy in 61% of each arm.

In terms of the safety profile, 95% of all treatment-emergent adverse events (TEAEs) with nirogacestat were grade 1/2 -- the most frequent of which being diarrhea, nausea, fatigue, hypophosphatemia, and rash.

Grade ≥3 TEAEs were substantially more frequent with nirogacestat (57% vs 17% with placebo). Treatment discontinuation in the nirogacestat arm was required in 20% of cases -- primarily due to stomatitis, diarrhea, and rash. Benefit with the gamma secretase inhibitor was still observed in the 42% of patients needing a dose reduction. One TEAE-related death was reported in the placebo arm.

Of note, ovarian dysfunction occurred in three-fourths of women of childbearing age treated with nirogacestat (median time to onset of 9 weeks). Ovarian dysfunction (a composite representing changes in female hormone levels and clinical manifestations) resolved in all 11 women who discontinued the treatment after experiencing the AE.

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