Desmoid Tumors: The Tumor That Isn’t a Cancer

Dale Shepard, MD, PhD

Desmoid tumors, also known as aggressive fibromatosis, share some characteristics with cancers, specifically unchecked cell growth. However, it is not accurate to call them a cancer. That is the first thing Dale R. Shepard, MD, PhD, says to patients who are referred to his care at the Cleveland Clinic Taussig Cancer Center.

“We put desmoid tumors in the category of aggressive benign tumors,” Shepard said. “They’re kind of like cancers because they grow in an uncontrolled way. They’re not like cancers, because they don't invade into nearby structures, and they don't metastasize. They can grow and cause some troubles, but they wouldn't be considered a cancer. Historically, some of the treatments that we use to treat desmoid tumors are some of the drugs that we also can use to treat cancer. That’s one of the reasons oncologists are called upon to treat [desmoid tumors].”

Shepard is director of the Sarcoma and Phase I Programs at the Taussig Cancer Center at Cleveland Clinic. In his practice, he primarily deals with desmoid tumors associated with hereditary familial adenomatous polyposis, which results in colorectal cancer if left untreated.

Desmoid tumors are mesenchymal neoplasms that are locally invasive but do not metastasize. They are rarely life threatening, but the condition can be “destructive” and lead to severe pain and functional impairment. Desmoid tumors are typically diagnosed in young adults—the incidence is greatest in those aged 35 to 40 years. Women in this age group are particularly susceptible.¹

Desmoid tumors constitute 0.03% of all tumors, according to the National Organization for Rare Disorders. The estimated incidence in the general population is 2 to 4 per million people per year.²

These tumors are rarely fatal. In a retrospective study of 189 patients, the 5-year survival rate was 96%, and 87% of patients were still alive at 15 years. However, the actuarial relapse rate following surgical excision was 38% at 5 years. Even among patients with negative margins, the 10-year recurrence rate was 27%.³

In the 2010s, investigators learned that alterations of the Wnt/APC/β-catenin pathway drive desmoid tumors. To date, 2 types of these tumors have been identified: sporadic desmoid tumors associated with mutations of CTNNB1 and those associated with germline mutation of APC. These molecular alterations are thought to be mutually exclusive.⁴

The disease can be difficult to identify, and up to one-third of patients are misdiagnosed initially. Desmoid tumors can appear in any part of the body in different types of connective tissues, including muscle, fascia, and aponeurosis. Tumors appearing in the abdominal wall and extra-abdominal locations may present as painless mass. Larger lesions and those adjacent to neurovascular structures may be associated with pain and functional impairment.⁴ Shepard added that physicians may fail to consider the possibility of tumor in young patients, especially those who present complaining of pain.

Surgery and Systemic Therapy

The disease course is unpredictable. Patients can have spontaneous regression, long-lasting stable disease, or disease progression. Furthermore, physicians lack reliable and validated predictive factors for tumor growth.⁴

Desmoid tumors are primarily treated with surgery, with or without radiation therapy. Despite surgical resection, these tumors have a high rate of local recurrence—up to 30% of patients see their disease return.²

No FDA-approved agents are available for desmoid tumors at present. However, investigators have explored non-steroidal anti-inflammatory agents with some success. In one retroactive study of 20 patients treated with meloxicam, the partial response (PR) rate was 25.0% and 40.0% of patients achieved stable disease.⁵

Shepard said TKIs such as imatinib (Gleevec), pazopanib (Votrient), and sorafenib (Nexavar) have shown promise in these patients. In a German Interdisciplinary Sarcoma Group study, 38 patients received imatinib at 800 mg daily over 2 years. The primary end point of the study was progression arrest rate after 6 months (PAR6_mo).⁶

The PAR6_mo was 65%. Investigators observed 7 PRs at 21 months; the overall response rate was 19%. Eight patients who experienced disease progression received nilotinib (Tasigna) at 800 mg daily. PAR at 3 months was 88% in this group and investigators observed no more disease progressions until end of study.

In a double-blind, phase 3 trial (NCT02066181) published in 2018, investigators randomly assigned patients with progressive, symptomatic, or recurrent desmoid tumors to receive sorafenib 400 mg once daily (n = 50) or matching placebo (n = 37). A total of 84 patients were included in the efficacy analysis.⁷

At a median follow-up of 27.2 months, the median progression-free survival (PFS) was not reached in the sorafenib arm compared with 11.3 months (95% CI, 5.7–not evaluable [NE]) in the placebo arm. The estimated 2-year PFS rate was 81% (95% CI, 69%-96%) with sorafenib vs 36% (95% CI, 22%-57%) with placebo.

At the 2022 ESMO Congress, investigators presented findings for the experimental gamma secretase inhibitors AL102 and nirogacestat that Shepard found very encouraging. He noted that there has been little movement in desmoid tumor treatment since data were presented supporting the use of pazopanib and sorafenib in 2018.

“It’s a bit like feast or famine,” he said. “[Gamma secretase inhibitors] really look like the most promising target being tested right now, and it looks like we have 2 drugs that really could significantly change the landscape in how we manage patients.”

In the ongoing phase 2/3 RINGSIDE trial (NCT04871282), 31 patients were assigned to AL102 at 1.2 mg once daily. Thirty patients remained on treatment as of the data cutoff of February 22, 2022. Investigators observed 1 PR per RECIST criteria at week 16 that was confirmed at week 28. There were three other unconfirmed PRs recorded, 2 at week 28 and 1 at week 40. Seven of 9 patients experienced tumor volume reduction at week 16.^8,9

Shepard said that desmoid tumor treatments tend to work slowly, and he expects responses to improve over time.

“This RINGSIDE trial is still very early in development. The drug is still known by letters and numbers, AL102,” he added. “When we think about responses, you have to put that in the perspective of, even in common cancers where we use chemotherapies that we all are aware of, sometimes the response rates are pretty low. Sometimes the actual number of patients that have tumor shrinkage can be in the 10% [to] 20%. As such, as an overall response, some of these actually look pretty promising.”

In the phase 3 DeFi trial (NCT03785964), investigators assigned patients with progressive desmoid tumors to nirogacestat at 150 mg daily (n = 72) or placebo (n = 70). Investigators observed a significant PFS benefit in the experimental arm vs the control arm (HR, 0.29; 95% CI, 0.15-0.55; P < .001). The objective response rates in the nirogacestat and placebo arms were 41% (95% CI, 30.2%-54.5%) and 8% (95% CI, 3.1-%-17.3%), respectively; the complete response rates were 7% vs 0%, respectively, again favoring the experimental arm. The median time to response was 5.6 months (95% CI, 2.6-19.4) vs 11.1 months (95% CI, 2.8-16.4), respectively.¹⁰

Furthermore, nirogacestat induced early and durable improvements that were statistically and clinically significant in all prespecified patient-reported outcomes. Of the adverse effects reported in the experimental arm, 95% were grade 1/2.

“There was a 71% reduction in risk of progression, which is huge,” Shepard said. “That’s a really big response in terms of being able to give a therapy and have a really long period of time before the patient starts to progress compared with placebo.”

References

1. Penel N, Coindre J-M, Bonvalot S, et al. Management of desmoid tumours: a nationwide survey of labelled reference centre networks in France. Eur J Cancer. 2016;58:90-96. doi:10.1016/j.ejca.2016.02.008
2. Rare disease database: desmoid tumor. National Organization for Rare Disorders. Accessed September 22, 2022. https://bit.ly/3S8prym
3. Ballo MT, Zagars GK, Pollack A, et al. Desmoid tumor: prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy. J Clin Oncol. 1999;17(1):158-167. doi:10.1200/JCO.1999.17.1.158
4. Penel N, Chibon F, Salas S. Adult desmoid tumors: biology, management and ongoing trials. Curr Opin Oncol. 2017;29(4):268-274. doi:10.1097/CCO.0000000000000374
5. Cho JY, Gupta S, Cho HS, et al. Role of nonsteroidal anti-inflammatory drug in treatment of extra-abdominal desmoid tumors. Clin Orthop Surg. 2018;10(2):225-233. doi:10.4055/cios.2018.10.2.225
6. Kasper B, Gruenwald V, Reichardt P, et al. Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG). Eur J Cancer. 2017;76:60-67. doi:10.1016/j.ejca.2017.02.001
7. Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for advanced and refractory desmoid tumors. N Engl J Med. 2018;379(25):2417-2428. doi:10.1056/NEJMoa1805052
8. Gounder MM, Jones RL, Chugh R, et al. Initial results of phase II/III trial of AL102 for treatment of desmoid tumors (DT). Ann Oncol. 2022;33(suppl 7):S2337-S1228. doi:10.1016/j.annonc.2022.07.1591
9. Ayala Pharmaceuticals presents positive interim data from RINGSIDE pivotal phase 2/3 trial of AL102 in desmoid tumors at ESMO Congress 2022. News release. Ayala Pharmaceuticals, Inc. September 12, 2022. Accessed September 22, 2022. https://bit.ly/3UyV4CE
10. Kasper B, Ratan R, Alcindor T, et al. DeFi: A phase III, randomized controlled trial of nirogacestat versus placebo for progressing desmoid tumors (DT). Ann Oncol. 2022;33(suppl 7):S1435-S1436. doi:10.1016/j.annonc.2022.08.075