First FDA-Approved Drug for Desmoid Tumors: Nirogacestat

For adults with progressive desmoid tumors requiring systemic treatment, the US Food and Drug Administration (FDA) approved nirogacestat (Ogsiveo, SpringWorks Therapeutics, Inc.) on November 27, 2023.

This is the first treatment approved for desmoid tumors.

Desmoid tumors, also called aggressive fibromatosis, are rare, slow-growing soft tissue tumors that grow locally and generally do not metastasize. Usually asymptomatic, they can sometimes cause loss of organ function. With a very low annual incidence, desmoid tumors may arise particularly in association with genetic conditions such as Gardner syndrome and under the influence of the female hormone estrogen. Diagnosis involves imaging and biopsy, and treatment generally includes surgery. However, observation and follow-up may also be preferred when tumor size and symptoms are absent. Radiotherapy and various drug treatments may be used in advanced or recurrent cases. 

How Does Nirogacestat Work?

Nirogacestat inhibits the activity of an enzyme called gamma-secretase.

Gamma-secretase plays a critical role in the maturation of proteins that regulate intracellular signaling pathways and influence important functions such as cell growth, differentiation, and programmed cell death. This enzyme is necessary in the Notch signaling pathway and other signaling pathways, where it enables the activation of proteins involved in signaling.

The Notch pathway is particularly important in cancer biology. In several cancers, it has been found to be overactivated, contributing to uncontrolled cell proliferation and tumor development. By inhibiting gamma-secretase, nirogacestat prevents overactivation of this signaling pathway and suppresses cancer cell growth.

This mechanism is considered a therapeutic target, particularly in conditions involving gamma-secretase, such as desmoid tumors and certain other cancers. Nirogacestat is being developed and tested in clinical trials as a treatment strategy intended to stop or slow tumor growth by inhibiting Notch signaling.

Below, you can see the complex structure of the Notch signaling pathway and new treatment efforts in this area:

FDA Approval Based on the DeFi Study

Efficacy was evaluated in DeFi, an international, multicenter, randomized (1:1), double-blind, placebo-controlled study of 142 patients with progressive desmoid tumors unsuitable for surgery. Patients whose desmoid tumors progressed within 12 months from screening were eligible. Patients received nirogacestat 150 mg or placebo twice daily until disease progression or unacceptable toxicity.

The main efficacy outcome measure was progression-free survival (PFS) .

Results

Median PFS was not reached (NR) in the nirogacestat arm (95% CI: NR, NR) and was 15.1 months in the placebo arm (95% CI: 8.4, NR) (hazard ratio [HR] 0.29 [95% CI: 0.15, 0.55]; p-value=<0.001). An exploratory analysis of PFS based only on radiographic progression showed a hazard ratio of 0.31 (95% CI: 0.16, 0.62).

An additional efficacy outcome measure was objective response rate (ORR). In the nirogacestat arm, ORR was 41% (95% CI: 29.8, 53.8), compared with 8% (95% CI: 3.1, 17.3) in patients receiving placebo (p-value=<0.001).

The most common adverse reactions were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis (mouth sores), headache, abdominal pain, cough, alopecia (hair loss), upper respiratory tract infection, and shortness of breath.

Note: "Ovarian toxicity" refers to adverse effects of a drug or treatment on the ovaries in the female reproductive system. This toxicity may disrupt normal ovarian function, cause hormonal imbalances, or lead to structural damage to the ovaries.

The recommended nirogacestat dose is 150 mg taken orally twice daily, with or without food, until disease progression or unacceptable toxicity. Each 150 mg dose consists of three 50 mg tablets.

The efficacy of different treatment regimens used for desmoid tumors is shown below:

(*) Median progression-free survival has not yet been reached for these patients.

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Image description: The article's image was generated by ChatGPT 4.0 using the prompt: "An illustration showing dozens of intracellular signaling pathways"

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FURTHER READING: Signaling Pathways in Cancer

Below is a summary of 10 key signaling pathways involved in cancer development and their roles in cancer therapeutics:

1. Hippo Pathway: Regulates cell growth and organ size. Abnormal activation may lead to excessive cell growth and cancer.
2. Nrf2 Pathway: Protects cells against oxidative stress and harmful substances. Dysregulation may protect cancer cells from oxidative stress and allow them to develop chemotherapy resistance.
3. PI3K/Akt Pathway: Transmits signals for cell growth and survival. Overactivation occurs in many cancers and may cause uncontrolled cell proliferation.
4. Myc: A transcription factor that regulates cell growth and metabolism. Overexpression of the Myc gene promotes cell proliferation and is associated with cancer.
5. Notch Pathway: Regulates cell differentiation and plays a role in the development of many tissues and organs. Abnormal activation of the Notch pathway may contribute to certain cancers.
6. p53: Pauses the cell cycle when DNA is damaged and triggers repair or cell death (apoptosis). When the p53 pathway is disrupted, cells with damaged DNA may survive and become cancerous.
7. Cell Cycle: A series of mechanisms regulating cell division. Loss of control over these mechanisms leads to uncontrolled cell division, a hallmark of cancer.
8. RTK-RAS Pathway: This pathway comprises receptor tyrosine kinases (RTKs) and RAS proteins that regulate cell growth and differentiation. Mutations in it, particularly KRAS mutations, are common in many cancers and cause abnormal cell growth.
9. TGF-β: Inhibits cell growth and regulates differentiation. Disruption of the TGF-β pathway may lead to loss of tumor-suppressing effects and cancer progression.
10. Wnt Pathway: Regulates cell differentiation and tissue morphogenesis. Dysregulation of the Wnt signaling pathway has been associated with various diseases, including cancer.