Conference Coverage

First drug for desmoid tumors: ‘Impressive’ data for nirogacestat



PARIS – Desmoid tumors are rare, locally aggressive, soft-tissue tumors for which there is no approved systemic therapy – but a novel drug may become the first.

Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.

Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.

The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.

Trial results were presented at the annual meeting of the European Society for Medical Oncology.

Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.

There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.

Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”

With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”

Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.

“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”

However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”

Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.

Large trial in rare cancer

DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.

“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,” he said, adding that the findings are “practice changing.”

Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”

“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.

Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.

Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.


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