Andrew S. Brohl, MD

Local recurrence and progression of desmoid tumors, or aggressive fibromatosis, is common and can lead to significant morbidity. The DeFi study represents the largest randomized trial to date in this rare tumor type.

Objectively, there is clear antitumor activity of nirogacestat in this disease. If this agent becomes available, I would certainly consider it a treatment option — one of a growing list — for this disease. However, even if registration is achieved, a number of questions remain regarding the impact and utility of nirogacestat for the treatment of desmoid tumors.

First and foremost, a large number of effective treatment alternatives already exist, so it is unclear where nirogacestat might fit in the overall existing treatment schema. Although challenging to compare across studies, the disease activity of nirogacestat in the DeFi study appears to be similar to that reported in prospective trials for commonly utilized tyrosine kinase inhibitors pazopanib (Votrient, Novartis) and sorafenib (Nexavar, Bayer) , as well as to historical reports of efficacy of cytotoxic chemotherapy, especially anthracycline-based. Further, an increasing arsenal of locally directed therapies, including radiation therapy, cryoablation and high-frequency ultrasound, have all been reported to have very high disease control rates and might spare the patient exposure to systemic toxicity risks.

Given the nonmetastatic and rarely life-threatening nature of desmoid tumors, therapy selection is often dictated as much by toxicity perception among patients and providers as it is by the relative and unproved efficacy difference among available active therapies. In this aspect, as well, further detail and follow-up for patients treated with nirogacestat will be needed to help weigh this option compared with existing alternatives.

Although most toxicities associated with nirogacestat reported on the DeFi study were low grade, all low-grade toxicities are not created equal, and some may not be tolerable for patients dealing with a nonlife-threatening disease. Further, preclinical work and the early development of gamma secretase inhibitors for Alzheimer’s disease — before failing to help that condition to date and being repurposed for oncologic therapy — raised the concern that this drug class can lead to immunosuppressive effects via the inhibition of Notch signaling in effector lymphocytes. Perhaps as a result of the T-cell immunosuppressive effects, a significant increase in nonmelanoma skin cancers was observed following treatment with the gamma secretase inhibitor semagacestat among 1,537 patients in the phase 3 randomized trial for the treatment of Alzheimer’s disease. Further follow-up with nirogacestat will be needed to assess whether this class effect extends to this agent.

In summary, nirogacestat is the first gamma secretase inhibitor to demonstrate efficacy in a phase 3 randomized trial and, thus, will likely represent the first registered agent of this class. This would be a welcome addition to the menu of treatment options for desmoid tumors and perhaps will spur further development of this drug class in oncology more broadly. Questions remain as to where this option might fit among the myriad of current treatment alternatives for desmoid tumor, and further experience and follow-up will be needed to assess the toxicity and management concerns that are specific to this drug and class.

Reference:
Doody RS, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1210951.

Jean-Yves Blay, MD, PhD

The results show benefit for the first time with a novel treatment with a new mode of action in patients for whom treatment options are currently limited.

The findings are practice changing. We are going to use nirogacestat as part of the treatment armamentarium for patients with desmoid tumors. But we will have to figure out how best to use it.

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 centers, and it demonstrated the importance of targeting the right patients with the right drug when designing clinical trials.

The trial included patients with volumetrically progressive disease, which provided a measurable way to select patients in need of treatment. 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. The number of patients with cancer being referred to reference centers is increasing but could still be better in some regions, improving the outlook for patients with rare cancers.