‘Potential new standard’ for desmoid tumor progression

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

Internationally Challenge study involving more than 140 patients, the risk of 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 on placebo (HR 0 .29, 95% CI 0.15-0.55 , P

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

There is a “clear mechanistic rationale” for using nirogacestat in this disease setting, Kasper said, because desmoid tumors strongly express Notch, which can be blocked by gamma secretase inhibitors.

The objective response rate was significantly higher with nirogacestat (41% versus 8% with placebo, P

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

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

But tumor control isn’t the only goal for patients with desmoid tumors, Kasper said. “Improving symptom burden is even more important.”

In DeFi, treatment with nirogacestat significantly reduced pain and severity of disease symptoms, and improved physical functioning and quality of life, he said. “These improvements happened very early and were maintained throughout the trial,” said Kasper, who noted that about 40% of trial participants had uncontrolled pain at baseline.

“This improvement [in pain] is probably the most significant observation from this clinical trial, even though it was a secondary objective,” said Jean-Yves Blay, MD, PhD, of the Lyon Cancer Center in France, participating in ESMO.

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

“The symptomatic benefit in non-progressive tumors is not addressed in this trial,” Blay pointed out. “Many desmoid tumors do not have progression according to RECIST. If they would benefit [with nirogacestat] is probable, but not demonstrated here.”

DeFi (Desmoid/Fibromatosis) was a double-blind phase III trial that randomized 142 patients with progressive desmoid tumors at 37 sites in North America and Europe to 28-day cycles of nirogacestat twice daily (150 mg) or a 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-naïve tumors not amenable to surgery, or if they were refractory or had recurrent disease after a prior line of treatment.

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 the severity of desmoid tumor specific symptoms (DTSS) on GODDESS; and in physical and role functioning, also on GODDESS (P

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

With nirogacestat, physical functioning and role were also significantly improved on the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 (PP=0.007).

Base specs were generally well balanced between the two arms, Kasper said. The median age was 34, and about two-thirds were female. Groups were stratified by intra-abdominal (25%) and extra-abdominal (75%) tumor site. Approximately 40% of patients in both arms had multifocal disease, and of those analyzed, 79% to 84% had CTNNB1 mutations and 21% to 22% had APC changes.

For prior treatments, 26% of patients in the study group were treatment naïve versus 19% of those in the placebo group. The median number of prior treatments among 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, with the most common being diarrhea, nausea, fatigue, hypophosphatemia, and rash. cutaneous.

Grade ≥3 TEAEs were significantly more frequent with nirogacestat (57% versus 17% with placebo). Discontinuation of treatment in the nirogacestat arm was required in 20% of cases, mainly due to stomatitis, diarrhea and rash. A benefit with the gamma-secretase inhibitor was still observed in the 42% of patients requiring dose reduction. One TEAE-related death was reported in the placebo group.

Of note, ovarian dysfunction occurred in three quarters of women of childbearing potential treated with nirogacestat (median time to onset 9 weeks). Ovarian dysfunction (composite representing changes in female hormone levels and clinical manifestations) resolved in the 11 women who discontinued treatment after undergoing IE.


The study was funded by SpringWorks Therapeutics.

Kasper disclosed its relationships with SpringWorks, Ayala, Bayer, Blueprint, Boehringer Ingelheim, GlaxoSmithKline (GSK) and PharmaMar, as well as the EORTC’s Soft Tissue and Bone Sarcoma group.

Blay has reported relationships with Abbvie, Amgen, ARIAD, AstraZeneca, Bayer, Bristol Myers Squibb, DDB Health, Eisai, Genomic Health, Gilead, GSK, Innate-Pharma, Janssen, Lilly, Merck Serono, Merck Sharpe & Dohme, Nanobiotix, Novartis, Novex, Onxeo, Pfizer, Pharmamar, PRA, Roche, Sanofi Aventis, Swedish Orphan, Takeda and Toray.

Valerie J. Wallis