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A New Tx Paradigm for DTs
A New Paradigm of Precision Medicine in Progressing Desmoid Tumors

Released: January 25, 2023

Expiration: January 24, 2024

Robin L. Jones
Robin L. Jones, BSc, MBBS, MRCP, MD (Res)
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Key Takeaways
  • Active surveillance is the initial management recommendation for the majority of patients with desmoid tumors.
  • Treatment options for desmoid tumors include surgery, radiation, chemotherapy, and tyrosine kinase inhibitors, but no systemic therapy has received regulatory approval for this indication to date.
  • Gamma secretase inhibitors have shown promising results in prospective, randomized clinical trials for the treatment of progressive desmoid tumors.

In this commentary, Robin L. Jones, BSc, MBBS, MRCP, MD (Res), reviews the treatment paradigm shift in desmoid tumors (DTs), as well as exciting targeted therapies on the horizon.

DT is an invasive, proliferative disease of the connective tissues characterized by a variable and often unpredictable clinical course. There are approximately 5-6 cases per 1 million people per year, with a peak age of approximately 30 years. The disease occurs more often in women. In 90% to 95% of cases, DTs are sporadic (driven by mutations in CTNNB1 or β-catenin), and in 5% to 10% of cases they arise in the context of familial adenomatous polyposis driven by mutations in APC.

DTs usually grow as a single lesion and do not metastasize. They can result in tissue infiltration and lead to chronic pain, functional impairment, decreased quality of life, and―very rarely―death.

Over the past 2 decades, the management of DTs has changed. Due to the unpredictable clinical behavior of these tumors and the fact that they can spontaneously regress, active surveillance (with pain control) is now considered the initial management approach in the majority of patients. In addition, recurrence rates are high even after complete surgical resection. If there is evidence of clinical or radiologic disease progression on active surveillance, then systemic therapy can be considered. In the case of abdominal wall tumors, surgery can be considered, as the rate of recurrence following surgery at this anatomic site is low.

Numerous systemic therapies have activity in DTs, including but not limited to doxorubicin, pegylated liposomal doxorubicin, methotrexate plus vinblastine, vinorelbine, pazopanib, and sorafenib. The efficacy of most of these agents has been documented in retrospective case series. However, none of these agents has received regulatory approval for the treatment of DTs.

A randomized, placebo-controlled phase III trial evaluated sorafenib in patients with progressing DT. This trial showed a significant difference in median progression-free survival (PFS) for sorafenib compared with placebo (not estimable vs 11.3 months; HR: 0.13; P <.001). Despite the rarity of DTs, it is possible to perform randomized trials for this disease.

Subsequently, there have been many exciting developments in the management of DTs. Gamma secretase inhibitors have activity in this disease. A global randomized, placebo-controlled phase III trial of the gamma secretase inhibitor nirogacestat has been performed (NCT03785964). Patients with progressive DTs were eligible to enter the trial. Patients could be treatment naive or have disease refractory to therapy. The primary endpoint of the trial was PFS, and patients were randomized 1:1 to receive either nirogacestat or placebo. Stratification was by tumor location. There was significantly longer median PFS in the nirogacestat arm compared with placebo (not estimable vs 15.1 months; HR: 0.29; P <.001). Nirogacestat was well tolerated overall. Because of the age of many patients with DTs, ovarian suppression is an adverse event of gamma secretase inhibitors that requires careful monitoring.

AL102 is another gamma secretase inhibitor currently being evaluated in a randomized, placebo-controlled phase III trial (NCT04871282). The phase II component of this trial evaluated 3 doses of AL102, with deep, durable responses seen with all 3 doses and a manageable safety profile. AL102 at a dose of 1.2 mg daily was selected as the optimal dose for the placebo-controlled phase III portion of the study.

Furthermore, cryoablation also has been evaluated as a local therapy option in recurrent DTs. A prospective phase II trial has documented the safety and efficacy of this treatment modality in this disease (NCT02476305).

In conclusion, active surveillance is the initial management of most patients with DTs. Several systemic therapies have activity in this disease. Over the past few years, numerous prospective trials have been conducted for progressive DTs. The phase III trial of nirogacestat clearly showed the efficacy of this agent in DTs. In addition, another effective gamma secretase inhibitor (AL102) is being evaluated in a randomized, placebo-controlled phase III trial. Over the next few years, it is hoped that there will be further advances in the treatment of DTs, which will improve patient outcomes.

Learn More
To learn more about emerging precision medicine therapies in progressing DTs, read a text module and download the associated slideset from Bernd Kasper, MD, PhD.

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