Update: On November 27, 2023, the U.S. Food and Drug Administration approved nirogacestat (Ogsiveo™) for adults with desmoid tumors that cannot be treated with surgery alone. The approval was based on research led by investigators at Memorial Sloan Kettering Cancer Center. Nirogacestat is the first targeted therapy ever to be approved for desmoid tumors.
The targeted therapy nirogacestat demonstrated rapid and sustained improvements for adults with progressing desmoid tumors, according to results from a phase 3 clinical trial published March 9 in The New England Journal of Medicine. (1)
The DeFi trial randomized 142 patients with desmoid tumors (or aggressive fibromatosis) to receive oral treatment with either a placebo or nirogacestat, an investigational, selective gamma-secretase inhibitor that blocks Notch pathway signaling and cell growth. (2) SpringWorks Therapeutics Inc. developed nirogacestat and funded the trial conducted at Memorial Sloan Kettering Cancer Center (MSK) and 51 other sites worldwide (NCT03785964).
Highlights of the outcomes for nirogacestat versus placebo were as follows: (1)
- The objective response rate (ORR) was 41% versus 8%.
- The event-free probability at two years was 76% versus 44%.
Notably, the trial embedded the first patient-reported outcomes (PROs) tool for desmoid tumors: the Gounder/DTRF Desmoid Symptom/Impact Scale (GODDESS)™ , developed at MSK. (3) Patients reported significant improvements in pain, symptom burden, physical functioning, and health-related quality of life. Nirogacestat frequently induced side effects. However, 95% were grade 1 or grade 2 and considered manageable. (1)
“Rapid and sustained response to this treatment in patients with locally aggressive and invasive desmoid tumors is exciting,” says medical oncologist Mrinal Gounder, MD, an expert in treating soft tissue sarcomas and lead author of the paper. “At the same time, improving patients’ symptoms and health-related quality of life is essential. The results from this trial demonstrate strength in both aspects.”
Desmoid Tumors and Current Treatment Options
Desmoid tumors, also known as aggressive fibromatosis, are rare mesenchymal tumors. Despite being nonmetastatic, they are locally aggressive and invasive, causing low mortality yet substantial morbidity. (3), (4), (5), (6) The median age of patients diagnosed with the condition is 30 to 40 years. (5), (7) About 900 patients are diagnosed annually in the United States.
Desmoid tumors may compress vital structures, resulting in severe pain, nerve damage, functional impairment, and bowel obstruction or perforation. (3), (4), (8), (9), (1), (11), (12) In turn, these morbidities have a negative impact on quality of life and psychosocial functioning. (9), (13) Pain associated with disease progression may lead to opioid dependence or suboptimal pain management due to worries about opioid dependency. (14), (15)
Desmoid tumors may compress vital structures, resulting in severe pain, nerve damage, functional impairment, and bowel obstruction or perforation. (3), (4), (8), (9), (11), In turn, these morbidities have a negative impact on quality of life and psychosocial functioning. (9), (13) Pain associated with disease progression may lead to opioid dependence or suboptimal pain management due to worries about opioid dependency. (14) (15)
Managing desmoid tumors is challenging due to variable presentation and unpredictable progression. (16), (17) Currently, there are no approved therapies. Treatment approaches include active surveillance, surgery, chemotherapy, tyrosine kinase inhibitors, radiation, or local ablation. (17), (18) Surgery has become less common due to its high morbidity and postsurgical response rates of up to 50% to 88%. (17), (19), (20)
Nirogacestat: A Targeted Therapy
Nirogacestat is a gamma-secretase inhibitor, a drug class initially developed for treating Alzheimer’s disease that was not successful. More recently, researchers have been investigating gamma-secretase inhibitors in nonclinical cancer studies for their ability to block Notch signaling and cell growth. (21), (22), (23), (24), (25)
Desmoid tumors are characterized by overexpression of beta-catenin and Notch1 proteins, with cross talk between these pathways contributing to tumor proliferation. (26), (27), (28), (29) In previous phase 1 and phase 2 trials, nirogacestat showed anti-tumor activity in patients with desmoid tumors, and patients reported less pain. (30), (31), (32)
The DeFi trial evaluated the safety and efficacy of nirogacestat versus placebo in patients 18 years or older with a histologically confirmed diagnosis of progressing desmoid tumors, defined as 20% or greater progression, according to the Response Evaluation Criteria in Solid Tumors version 1.1, within 12 months of screening. (1)
Eligible patients were either treatment-naive with tumors unsuitable for surgery or had recurrent or refractory tumors after at least one line of therapy. A total of 70 patients received oral nirogacestat 150 mg, and 72 patients received a placebo twice daily, taken continuously in 28-day cycles, starting from May 2019 to August 2020. (1)
The primary end point was progression-free survival (PFS), defined as the time from randomization to the date of image-based or clinical progression compared with baseline. Secondary end points included ORR and partial response rate, and PROs according to the GODDESS™ Desmoid Tumor Symptom Scale total symptom score, the GODDESS™ Desmoid Tumor Impact Scale physical functioning score, and the European Organisation for Research and Treatment of Cancer quality of life questionnaire core 30 (EORTC QLQ-30) scores for global health and quality of life, physical functioning, and role functioning. (33), (34) The trial also includes longer-term follow-up of reproductive function, as most patients were of childbearing age. (1)
Results and Implications
Nirogacestat demonstrated a significant improvement in PFS compared with placebo: The probability of being event-free at two years was 76% versus 44% (hazard ratio: 0.29, p<0.001). ORR was significantly higher in the nirogacestat group at 41% compared with 8% in the placebo group (p<0.001), with a median time to response of 5.6 months versus 11.1 months, respectively. The complete response was 7% with nirogacestat versus 0% with the placebo. (1)
Patients treated with nirogacestat reported signficant improvements in several secondary PROs, including pain, symptom burden, physical role and functioning, and health-related quality of life (p<0.015). (1)
Frequent side effects of nirogacestat were diarrhea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%). Overall, 95% of adverse events were grade 1 or grade 2 but led to discontinuation in 20% of patients. Note that 27 of 36, or 75%, of women of childbearing age experienced ovarian dysfunction, which resolved in 20 patients (74% of 27). (1)
Advancing Care for Patients With Rare Desmoid Tumors
This study would not have been possible without advocacy by the Desmoid Tumor Research Foundation (DTRF). This nonprofit organization saw results suggesting nirogacestat might be effective for treating desmoid tumors soon before the manufacturer was going to abandon it, and worked with SpringWorks Therapeutics and the National Cancer Institute to develop clinical trials and recruit participants.
“The partnership with DTRF is an important part of this success story,” says Dr. Gounder, who serves as an advisor on the group’s Medical and Scientific Advisory Boards and was a member of the Desmoid Tumor Working Group that published a global consensus-based approach to treating patients with desmoid tumors in 2020. (18)
MSK is dedicated to advancing care for common cancers as well as rare and neglected tumors. Surgical oncologist Samuel Singer, MD, FACS, Chief of the Gastric and Mixed Tumor Service and the Vincent Astor Chair of Clinical Research, leads MSK’s Soft Tissue Sarcoma Disease Management Team, a multidisciplinary group of soft tissue pathologists, medical oncologists, and radiation oncologists who collaborate on each individual case to design the best treatment plan.
MSK is currently conducting 29 clinical trials for patients with soft tissue sarcomas. Dr. Gounder is the principal investigator leading two of these studies, including the RINGSIDE trial (NCT04871282), a multicenter phase 2/3 study of the investigational oral drug AL102 in patients with progressive desmoid tumors. The trial began in March 2021 and continues to enroll participants.
The DeFi phase 3 clinical trial was sponsored and funded by SpringWorks Therapeutics Inc. Dr. Gounder has provided services to Ayala Pharmaceuticals Inc.; Bayer; Boehringer Ingelheim; Guidepoint Global Advisors; Karyopharm; Med Learning Group; Rain Therapeutics Inc.; SpringWorks Therapeutics Inc.; Syneos Health; and UptoDate.