For the first time, a novel gamma secretase inhibitor has shown extremely promising results in desmoid tumors—a rare, benign, but potentially aggressive tumor type. This new treatment approach led to significant improvements in progression-free survival (PFS) and response rate, as well as reduced symptoms and better quality of life (QOL) in patients with these tumors, according to results of the DeFi trial presented at the European Society for Medical Oncology Congress 2022.
Worldwide, desmoid tumors occur in 3 to 5 cases per million annually. The disease course is unpredictable and although they are not generally fatal, these soft-tissue tumors are invasive and can lead to symptoms that negatively affect QOL. There is currently no treatment approved for this disease.
“Due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” said lead investigator Bernd Kasper, MD, PhD, Professor; Medical Director, Mannheim Cancer Center; and Coordinator, Oncology Center and Sarcoma Center, Universitätsmedizin Mannheim, Germany.
The Notch signaling pathway is implicated in the development and progression of many tumor types, including desmoid tumors. This pathway is blocked by gamma secretase inhibition, providing mechanistic rationale for nirogacestat in patients with the disease.
DeFi is a global, randomized, double-blind, placebo-controlled, phase 3 trial evaluating the activity and safety of nirogacestat in 142 patients with progressive desmoid tumors. Eligible patients had histologically confirmed desmoid tumors with progressive disease per RECIST version 1.1 criteria. Patients either had to be previously untreated and deemed unfit for surgery or had to have recurrent or refractory disease following 1 line of therapy.
“This is the largest and most rigorous randomized controlled study ever carried out in this tumor type,” Dr Kasper stated. “Results showed a statistically significant improvement in progression-free survival in patients [randomly assigned] to nirogacestat compared to the placebo group, with a 71% lower risk for disease progression on average.”
Patients were randomized 1:1 to treatment with nirogacestat 150 mg twice daily or matched placebo in 28-day cycles until radiographic disease progression, at which point those in the placebo arm could cross over to open-label nirogacestat. The primary end point was PFS, with secondary end points of objective response rate, QOL, and patient-reported outcomes (PROs) for pain, symptom burden, and physical and role function.
At a median follow-up of 19.2 months for nirogacestat (N = 70) and 10.9 months for placebo (N = 72), the median PFS was not estimable for nirogacestat and was 15.1 months for placebo, representing a statistically and clinically significant result (P <.001).
The response rate was 5 times higher with the novel agent—41% in the nirogacestat arm and only 8% in the placebo arm, all partial responses (P <.001). The complete response rate with nirogacestat was 7% and there were no complete responses in the placebo arm.
Nirogacestat was relatively well-tolerated. Almost all of the treatment-emergent adverse effects were grade 1 or 2 and emerged mainly during cycle 1 of therapy.
The study also measured PROs to determine the impact of this treatment on QOL. “We saw a statistically significant benefit in reduction of pain and symptom burden, and improvement in physical and role functioning and in health-related quality of life, which was really impressive. In providing treatment, we try to optimize local tumor control and reduce the symptom burden. But we have previously had no approved therapy for desmoid tumors. This study has the potential to lead to the first registration of a drug to treat patients with this disease,” Dr Kasper noted.
Formal discussant Jean-Yves Blay, MD, PhD, Professor, Medicine, University Claude Bernard, Lyon, France; and General Director, Centre Leon Bernard Comprehensive Cancer Center, Lyon, was enthusiastic about the results. “This is a unique study, very important in many aspects. The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited. The findings are practice-changing,” stated Dr Blay, adding that its optimal use remains to be established.