Significant improvement in progression free survival and response rate combined with reduced symptoms and better quality of life are reported as outcomes of a new treatment approach for patients with desmoid tumours, which are benign, but locally aggressive and invasive soft tissue tumours.

By targeting the Notch pathway with the novel gamma secretase inhibitor nirogacestat, researchers from the DeFi trial have obtained positive results for the first time with this approach. The results were reported at the ESMO Congress 2022.

Desmoid tumours are rare, with an incidence of 3-5 cases per million people worldwide each year. Patients have an unpredictable disease course and, although not generally fatal, the soft tissue tumours can cause symptoms that greatly impair quality of life.

“Due to local and aggressive growth, desmoid tumours can cause pain, disfigurement and functional problems that can be a real burden for patients,” said lead author Bernd Kasper, Mannheim Cancer Center, Germany.

The DeFi study included 142 patients with progressive desmoid tumours who were recruited from 37 centres across the world.

“This is the largest and most rigorous randomised controlled study ever carried out in this tumour type,” reported Kasper. “Results showed a statistically significant improvement in progression-free survival in patients randomised to nirogacestat compared to the placebo group, with a 71% lower risk of disease progression on average.”

The response rate was also much higher – 41% in the nirogacestat arm and only 8% in the placebo arm; nearly one in ten patients (7%) showed a complete response with the agent.

The study measured patient reported outcomes because of the major impact of desmoid tumours on quality of life. “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,” noted Kasper. “In providing treatment we try to optimise local tumour control and reduce the symptom burden. But we have previously had no approved therapy for desmoid tumours. This study has the potential to lead to the first registration of a drug to treat patients with this disease.”

“This is a unique study, very important in many aspects,” said Jean-Yves Blay, Cancer Center of Lyon, France, who was not involved in the study. “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 Notch signalling pathway is implicated in the development and progression of many tumour types.

“The findings are practise changing,” added Blay. He predicted: “We are going to use nirogacestat as part of the treatment armamentarium for patients with desmoid tumours. But we will have to figure out how best to use it.”

Remaining questions include which patients should be offered this treatment, where it fits in relation to current approaches, how to identify responders and the optimal duration of treatment. DeFi included patients with progressing tumours but both Blay and Kasper said that nirogacestat could also be considered in patients with pain and impaired functioning.

“This was a very smart study: it demonstrated the feasibility of carrying out a large, placebo-controlled trial - which is the highest quality clinical study to investigate the activity of an agent - in a rare cancer by recruiting patients from a multinational group of reference centres and it demonstrated the importance of targeting the right patients with the right drug when designing clinical trials,” Blay added.

“The trial included patients with volumetrically progressive disease, which provided a measurable way to select patients in need of treatment.” He added: “The success of this study puts even more emphasis to the concept of having patients with rare cancers referred into reference centres, where clinical studies can be accomplished in record times with the potential to deliver new treatments to patients with orphan diseases.”

The number of cancer patients being referred to reference centres is increasing but could still be better in some regions, improving the outlook for patients with rare cancers. 

Source: ESMO