FDA Approval of Nirogacestat Introduces First Systemic SOC Therapy for Desmoid Tumors

The recent FDA approval of the γ-secretase inhibitor nirogacestat (Ogsiveo) provides a long-awaited standard-of-care (SOC) therapy for patients with progressing desmoid tumors, addressing the previous lack of approved systemic therapies in this space, according to Mrinal M. Gounder, MD.

Nirogacestat’s FDA approval in this population was supported by findings from the phase 3 DeFi trial (NCT03785964).¹ Nirogacestat produced an estimated 2-year progression-free survival (PFS) rate of 76% (95% CI, 61%-87%) vs 44% (95% CI, 32%-56%) with placebo in patients with unresectable desmoid tumors.² The median PFS in the nirogacestat arm was not estimable (NE; 95% CI, NE-NE), and was 15.1 months (95% CI, 8.4-NE) in the placebo arm (HR, 0.29; 95% CI, 0.15-0.55; P < .001). PFS results were generally consistent across prespecified subgroups.

Additionally, nirogacestat elicited an overall response rate of 41% (95% CI, 29.8%-53.8%) vs 8% (95% CI, 3.1%-17.3%) with placebo (P < .001).1,2 Complete responses were observed in 7% and 0% of patients, respectively. Patient-reported outcomes, such as symptom burden, pain, physical or role functioning, and health-related quality of life, were also significantly improved in the nirogacestat arm (P ≤ .01).²

“This represents the first drug approved specifically for desmoid tumors by the FDA, in a phase 3 randomized, controlled study. This is also the first time that a gamma secretase inhibitor, which is a new class of drugs, is approved for any indication to treat human diseases,” said Gounder, who is a sarcoma oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York.

In an interview with OncLive®, Gounder discussed the rationale for investigating nirogacestat in the DeFi trial,highlighted patient-reported outcomes with the agent in this study, and discussed potential next steps for better utilizing T2-weighted magnetic resonance imaging (MRI]) in addition to RECIST criteria when assessing tumor volume and dimensions in desmoid tumors.

OncLive: What unmet needs did the DeFi trial of nirogacestat aim to ameliorate for patients with desmoid tumors?

Gounder: Desmoid tumors are rare tumors; there are only about 900 to 1,000 patients diagnosed with this rare disease annually in the United States. However, they have a very wide and heterogeneous presentation. [Prior to this approval] we didn't have a standard of care for these patients, so there were many ways to treat them. When it comes to systemic therapies, we didn't yet have any FDA approved drugs specifically for desmoid tumors.

The DeFi study set out to address that [unmet need] by conducting one of the largest phase 3 studies [in which patients were randomly assigned to] the novel gamma secretase inhibitor nirogacestat or placebo. The [investigators] looked at the activity of this novel class of agents in this rare disease.

What was the rationale for looking at tumor volume using MRI T2 signaling in the DeFi trial?

In oncology, the way we know whether a disease is responding to a drug is by using RECIST criteria. RECIST criteria is based on computed tomography or MRI changes in terms of the tumor's dimensions alone. Although resistance is a gold standard for evaluating tumor responses, it does not lend itself perfectly well to [representing] some forms of certain types of cancers, especially desmoid tumors. Desmoid tumors cross through many different fasciae, they are asymmetrical, and they have unusual shapes, which don't lend themselves easily to RECIST measurements. In many ways, we may be underestimating the efficacy of drugs by sticking to RECIST criteria alone. Therefore, we want to look beyond tumor dimensions, and we looked at tumor volume to see how much of the entire tumor itself shrinks rather than just the longest unidimensional measurements.

Beyond changes in the dimensions or the size, we also wanted to see what happens inside of the tumor. Does the drug change the tumor from a cellularly-active tumor to something that is inactive and collagenous? Both these components, especially the MRI T2 signal, are not picked up by the current gold standard, which is RECIST itself. By [assessing] these novel imaging biomarkers, such as MRI T2 signal changes as well as tumor volumes, we may be better able to capture the efficacy of drugs.

What key findings from the DeFi study demonstrated the efficacy and safety of nirogacestat in desmoid tumors?

Two posters [on data from the DeFi study were presented at the 2023 ASCO Annual Meeting]. One of these looked at the patient-reported outcomes and how nirogacestat vs placebo affects a patient's pain scales and other quality of life measures.

[Changes in tumor volume seen with this] radiographic imaging [approach] are also [significant] and have not been previously published. This is a novel finding in addition to the MRI T2 changes seen both on the placebo arm and the treatment arm.

What are some of the next steps for this research?

Continuing to go deeper into this space, linking patient-reported outcomes, PFS, and RECIST responses to T2 as well as tumor volume, and coming up with a new threshold for a significant MRI T2 signal change would be significant. Hypothetically speaking, we would then incorporate both MRI T2 signal changes as well as tumor volume as an end point for determining whether a disease is responding, especially in desmoid tumors.

What is your main message for colleagues regarding the significance of nirogacestat’s FDA approval for patients with desmoid tumors?

The first message is that randomized, controlled phase 3 studies are feasible in rare diseases, but this requires a global collaboration. People from across the world need to come together to accrue the right patients for this study. The second message is that [nirogacestat gives us] a new drug in the clinic. We should [use it] in the appropriate and carefully selected patients with desmoid tumors for whom it may be a viable [option].

References

1. FDA approves nirogacestat for desmoid tumors. FDA. November 27, 2023. Accessed November 30, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nirogacestat-desmoid-tumors
2. Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388(10):898-912. doi:10.1056/NEJMoa2210140