CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 15, 2023
Expiration: March 14, 2024
In this module, Bernd Kasper, MD, PhD, discusses emerging data for the treatment of progressing desmoid tumors.
Please note that the key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be downloaded here or by clicking on any of the slide thumbnails in the module alongside the expert commentary.
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Presurvey
Desmoid tumors are locally aggressive and invasive soft tissue tumors that are challenging to manage due to their variable presentation, unpredictable clinical course, and lack of currently approved therapies. When discussing desmoid tumors, we are talking about a rare disease. The incidence is approximately 5-6 cases per 1 million of the population per year. There is a peak age of approximately 30-35 years and the disease predominantly affects females.1-5
There is an annual incidence of approximately 1700 new cases in the United States, with the prevalence of the disease being much higher as it is rare for patients to die from this disease. 90% to 95% of desmoid tumors are sporadic, while 5% to 10% arise in the context of familial adenomatous polyposis. Desmoid tumors are characterized by mutations in CTNNB1 or APC.1-4
Clinically, desmoid tumors typically start as a painless or minimally painful mass with a history of slow growth. They grow as a single lesion and can result in tissue and organ infiltration. However, desmoid tumors do not metastasize. Desmoid tumors can lead to chronic pain, functional deficits and debility, disfiguration, psychologic problems, a general decrease in the patient’s quality of life (QoL), and in rare cases, death.1,4
There is a consensus initiative with the goal of harmonizing treatment guidelines and recommendations for desmoid tumors that started in 2014. Medical experts from the European Organization for Research and Treatment of Cancer (EORTC) and Soft Tissue and Bone Sarcoma Group (STBSG) came together with patient and patient advocates from Sarcoma Patients EuroNet (SPAEN) patient organization. The initial consensus from 2015 was updated in 2017, and then a global consensus meeting was held in 2018. This global consensus meeting was initiated by The Desmoid Tumor Working Group and involved medical experts as well as patients and patient advocates, not only from Europe but also from North America, Canada, and Japan. This meeting was supported by several organizations including the European Reference Network for rare solid adult cancers (EURACAN), EORTC/STBSG, SPAEN, and the Desmoid Tumor Research Foundation (DTRF). These global consensus recommendations were published in 2020 in the European Journal of Cancer.5
From the global consensus meeting, we developed a treatment algorithm for desmoid tumors. In general, there has been a paradigm shift in the treatment of desmoid tumor patients. Ten to 15 years ago, desmoid tumors were treated like malignant soft tissue sarcomas, often with very extensive surgeries. This has shifted to a much more conservative approach. Active surveillance is the initial approach in the majority of desmoid tumors patients, and we recommend therapy in the case of a subsequent progression, which can be either a systemic therapy or surgical resection. Systemic therapy is used for most patients, whereas surgical resection typically is reserved for those with abdominal wall tumors.5
The Desmoid Tumor Working Group no longer recommends using antihormonal therapies/nonsteroidal anti-inflammatory agents for the treatment of desmoid tumors. Systemic therapies available include chemotherapy, tyrosine kinase inhibitors (TKIs), and investigational agents, including gamma secretase inhibitors. Which treatment is selected should be individualized for each patient to optimize tumor control and improve symptoms.5
Nonresectable, rapidly growing, symptomatic (or even life threatening) desmoid tumors should preferably be treated with chemotherapy.
There are several chemotherapy regimens that may be used in desmoid tumor patients: methotrexate in combination with either vinblastine or vinorelbine,6,7 vinorelbine monotherapy,8 anthracycline based regimens (similar to soft tissue sarcoma patients),9 or pegylated liposomal doxorubicin.10-12 It is important to note that there are no randomized studies in desmoid tumors for these chemotherapy regimens. There are only rather small case series reports or small numbers of patients.2 Selecting a chemotherapy regimen should be individualized for each patient and long-term toxicities (cardiotoxicity, hypertension, infertility) of these agents should be taken into consideration.
TKIs are another treatment option for desmoid tumor patients. There have been numerous small, prospective, single arm studies using daily imatinib, but response rates have been limited (6%-19%).13
The Alliance A091105 trial was the first large, randomized phase III trial for treatment of desmoid tumors. Adult patients with advanced or refractory desmoid tumors were randomized in a 2:1 fashion to receive either sorafenib 400 mg once daily or placebo. Sorafenib was found to significantly prolong the primary endpoint of PFS compared with placebo, with a 2-year PFS rate of 81% in those who received sorafenib compared with 36% in those who received placebo (HR 0.13; 95% CI: 0.05-0.31; P <.001). The ORR for sorafenib was 33% compared with 20% in the placebo arm.
The most common adverse events reported with sorafenib were rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). 20% of patients discontinued sorafenib due to adverse events.14
Pazopanib is another TKI that has been tested in desmoid tumors in a trial from our French colleagues, called DESMOPAZ. DESMOPAZ is a multicenter, randomized, open-label phase II study where patients were randomly assigned to pazopanib 800 mg once daily for up to 1 year or the chemotherapy combination of methotrexate plus vinblastine (administered weekly for 6 months, then every other week for 6 months) in adult patients with progressive desmoid tumors. The primary endpoint was the PFS rate at 6 months, which was 84% for pazopanib compared with 45% for the chemotherapy combination (95% CI: 69.3-93.2).
The most common grade 3/4 adverse events noted in the trial were hypertension (21%) and diarrhea (15%) in the pazopanib arm compared with neutropenia (45%) and liver transaminitis (18%) in the methotrexate/vinblastine arm. Treatment discontinuation due to adverse events were similar between pazopanib and methotrexate/vinblastine at 23% and 27%, respectively.15
This table summarizes the different efficacies for the TKIs. The first 4 studies are all small studies of imatinib. The overall response rates are rather low, ranging from 6% to 19%. In comparison, the sorafenib trial had an overall response rate of 33% and the pazopanib trial exhibited an overall response rate of 37%.13
We see improved response rates with the TKIs and the convenience of an oral medication, but their use is sometimes hindered by tolerability and the potential for long-term adverse effects (hypertension).
The most recent emerging treatment strategy for desmoid tumors are the gamma secretase inhibitors. There is a clear mechanistic rationale for the use of gamma secretase inhibitors in desmoid tumors. Desmoid tumors highly express Notch.13 Crosstalk between the Notch pathway and the Wnt/β-catenin pathway has been observed as well as Notch pathway activation as a result of dysregulation from the Wnt/β-catenin pathway.16 The Notch pathway can be blocked by gamma secretase inhibitors.13 Inhibiting Notch can slow cell proliferation and induce apoptosis.17 There are 2 gamma secretase inhibitors currently under development for desmoid tumors: nirogacestat and AL102.
The first gamma secretase inhibitor that has been tested in desmoid tumors is nirogacestat. Nirogacestat is a selective, oral, investigational, small molecule gamma secretase inhibitor that has shown antitumor activity in desmoid tumors in phase I and II trials with a manageable adverse event profile.1 This was the basis for the DeFi study, results of which were presented during the Presidential session at the 2022 European Society of Medical Oncology (ESMO) Congress.
The DeFi trial was a global, randomized, double blind, placebo controlled phase III trial comparing the efficacy, safety, and tolerability of nirogacestat vs placebo in adult patients with progressive desmoid tumors. In the trial, 142 patients were randomized 1:1 across 37 sites in North America and Europe. The primary endpoint was PFS, and secondary endpoints included ORR and numerous PROs, including symptom burden, physical and role functioning, as well as overall QoL.18
The median age was rather young, as expected, at 34 years with a female predominance of 64% to 65%. Approximately 25% of patients in the nirogacestat and placebo treatment arms had intra abdominal tumors, with the remaining 75% being extra abdominal tumors. Most patients had relapsed or refractory disease, 74% in the nirogacestat arm and 81% in the placebo arm, with 61% of patients in each arm having already received previous systemic therapy.18
The primary endpoint of PFS was met in the DeFi trial. Nirogacestat statistically significantly reduced the risk of disease progression by 71% compared with placebo, with an impressive Kaplan-Meier curve. The median PFS for placebo was 15.1 months and was not reached for nirogacestat due to the low number of events (HR: 0.29; 95% CI: 0.15-0.55; P <.001).18
ORR was assessed by blinded independent central review throughout the study. The ORR for nirogacestat was 41% compared with 8% in the placebo arm (P <.001); 5 patients (7%) who received nirogacestat achieved a complete response compared with no complete responses in the placebo arm. The median time to objective response was 5.6 months (range: 2.6-19.4 months) with nirogacestat compared with 11.1 months (range: 2.8-16.4 months) for placebo.18
Nirogacestat significantly improved all secondary endpoints in this trial, including PROs. Nirogacestat significantly reduced pain (P <.001), which was assessed by the Brief Pain Inventory (Short Form).
Nirogacestat significantly reduced the desmoid tumor specific symptom severity (P <.001), which was assessed by a desmoid tumor specific PRO tool, called GODDESS.
Nirogacestat significantly improved patient physical/role functioning and overall QoL, which was assessed by the desmoid tumor specific GODDESS physical functioning impact score (P <.001). Moreover, nirogacestat also significantly improved the EORTC QLQ C30 physical functioning (P <.001), role functioning (P <.001) and global health status QoL (P = .007) compared with placebo at cycle 10.18
The most frequent adverse events with nirogacestat were diarrhea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%) and rash (32%). Diarrhea was the adverse event that had the biggest impact on patients’ daily lives. However, it can be well managed with over-the-counter antidiarrheals. In the study, 95% of all treatment emergent adverse events (TEAEs) were grade 1/2 and the first onset of most of these adverse events occurred very early, during the first cycle of therapy. Dose reductions resultant of TEAEs were necessary in 42% of patients in the nirogacestat arm.18
Ovarian dysfunction was an adverse event observed in this trial. Ovarian dysfunction is not a gamma secretase inhibitor-specific adverse event; we can see ovarian dysfunction in numerous other oncology treatments as well. Ovarian dysfunction was defined as changes in female reproductive hormone levels often accompanied by clinical manifestations; 27 of 36 (75%) women of childbearing potential reported symptoms of ovarian dysfunction. However, these symptoms resolved in 100% of patients who discontinued nirogacestat for any reason and 64% of patients who continued with ongoing nirogacestat therapy.18
In summary, DeFi represents the largest and most rigorous randomized controlled trial conducted to date in desmoid tumors. It also is the first clinical trial to demonstrate a benefit with a gamma secretase inhibitor in any indication.
Nirogacestat demonstrated rapid, sustained, and statistically significant improvements in all primary and secondary efficacy endpoints. Nirogacestat reduced disease progression by 71% and had an ORR of 41% compared with 8% in the placebo arm. The gamma secretase inhibitor exhibited a manageable safety profile with 95% of all TEAEs being grade 1/2.18
With these results, nirogacestat could gain the first regulatory approval for desmoid tumors and has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.
Nirogacestat was not the only gamma secretase inhibitor with data presented in 2022. Data from the phase II portion of the RINGSIDE study was presented at the 2022 ESMO meeting and CTOS meeting. RINGSIDE is investigating AL102, which is another oral, potent inhibitor of gamma secretase.
The RINGSIDE trial is a combined phase II/III trial evaluating AL102 in progressive desmoid tumors. Part A, the phase II portion of the study, compares 3 different doses of AL102: 1.2 mg once daily, 4 mg twice weekly, and 2 mg twice weekly until disease progression or withdrawal for any reason. The primary endpoint of Part A is safety. Part B, or the phase III portion of the study, is a double-blind, placebo-controlled study that will compare the dose selected in Part A with placebo. Results from Part A were presented in 2022.19
42 patients have been enrolled in RINGSIDE Part A. Baseline characteristics were well matched between the 3 dosing schedules. AL102 was generally well tolerated, with a manageable safety profile across the 3 dosing schedules. The most common adverse events seen were gastrointestinal disorders, fatigue, and skin disorders. Most adverse events were grade 1/2 and there were no grade 4/5 adverse events. Grade 3 adverse events were uncommon but were similar across the 3 arms. Adverse events causing discontinuation included diarrhea, stomatitis, alanine aminotransferase elevation, and rash. The adverse events seen with AL102 were very similar to those seen with nirogacestat.19
Tumor volume changes were seen in all dose groups at week 16. Responses as determined by central RECIST were also noted at week 16, which included 1 patient with a partial response (PR). Patient responses were noted to be durable and deepened over time, with 3 additional patients achieving a PR during the follow-up timeframe.19
MRI changes in T2 weighted signal intensity represent a decrease in tumor cellularity that is thought to be an indicator of antitumor efficacy. Of interest, a reduction of the T2 intensity could be demonstrated in 19 of 21 patients at week 16.19
Overall, AL102 was generally well tolerated with a manageable safety profile, with no grade 4/5 adverse events and most adverse events being grade 1/2. The Part A (phase II) efficacy was demonstrated across all arms with the first PR seen at week 16 and 3 additional PRs noted during the follow-up period. The RINGSIDE Part A phase II results support the initiation of Part B (phase III) with the 1.2 mg once daily dose to be compared with placebo. RINGSIDE Part B is currently ongoing and recruiting patients (NCT04871282).19
There are additional ongoing trials for the treatment of desmoid tumors. There is an ongoing trial evaluating nirogacestat in the pediatric patient population (NCT04195399). Tegavivint, a β-catenin inhibitor, currently is being tested in a phase I/II trial of relapsed/refractory solid tumors, including desmoid tumors, in the United States (NCT04851119). There are numerous other investigational trials ongoing to advance the treatment of desmoid tumors.
In summary, the Desmoid Tumor Working Group no longer recommends the use of antihormonal therapies.
Chemotherapy may be indicated in rapidly growing, symptomatic, or even life threatening desmoid tumors. The chemotherapy combination of methotrexate plus vinblastine is typically used in the pediatric population, as it has the most data in pediatric patients. TKIs have not been investigated in the pediatric setting for this disease state and therefore are used with caution. For younger adult patients, pegylated liposomal doxorubicin may be preferred as an anthracycline regimen due to its lower risk of cardiac toxicity. It is crucial to consider the long term toxicity of some of these chemotherapeutic agents when selecting therapy for patients. TKIs, such as sorafenib or pazopanib, demonstrated clinical activity in randomized studies and are used in clinical practice, but tolerability limits their use. Keep in mind, none of these treatment options have regulatory approval in any country for this indication, and therefore may not be available or reimbursed.
The emerging gamma secretase inhibitors (nirogacestat and AL102) show promise in being effective agents for the treatment of desmoid tumors with manageable safety profiles. Nirogacestat most likely will be the first health authority–approved drug in this indication and may become the standard of care for first line therapy for patients with desmoid tumors requiring systemic treatment. My opinion is the threshold to use nirogacestat will potentially be much lower in progressive or symptomatic desmoid tumor patients as it is a well-tolerated and very effective treatment option. It may even challenge the paradigm of active surveillance.
Assessment
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