Extended progression-free survival and long-term safety of nirogacestat in patients with desmoid tumors.

Abstract

11545 Background: Desmoid tumors are rare, locally invasive, soft-tissue neoplasms that can cause significant morbidity and frequently recur despite surgery or radiation. The ongoing phase II trial of nirogacestat, a gamma-secretase inhibitor, in patients (pts) with recurrent, refractory desmoid tumors (NCT01981551), has reported disease stabilization and multiple partial responses as assessed by RECIST criteria (Kummar JCO 2017). Herein, we report long-term outcomes, tolerability, and safety of this study. Methods: A total of 17 pts enrolled in this open label, single arm, phase II study, completing accrual in 2014. Pts received 150 mg nirogacestat orally twice a day in continuous 3-week cycles. Objective treatment response was defined by RECIST 1.1 at cycle 1 and every 6 cycles thereafter using CT (affected area) per the primary study objective; optional MRI assessment was concurrently performed. Yearly CT scans of the chest, abdomen, and pelvis were performed on pts starting in 2016. Results: As of Dec. 31, 2021, 4/17 (23%) pts remain on nirogacestat treatment for over 7 years. The objective response rate has not changed since the 2017 publication [31.25% (5/16 evaluable patients), with an exact two-sided Clopper-Pearson 95% confidence interval of 11.0-58.7%], but the observed extended progression-free survival (PFS) is notable; no RECIST disease progression has been observed for any of the 16 evaluable patients at any point on study. Median time on treatment was 4.14 years (range: 0.17-7.99 years). Most common adverse events remain hypophosphatemia (13/17, 76%; 8 grade 3 [gr3], 5 gr2), diarrhea (13/17, 76%; 1 gr3, 4 gr2, 8 gr1), nausea (11/17, 65%; 11 gr1), AST increase (11/17, 65%; 1 gr2, 10 gr1), and lymphopenia (11/17, 65%; 2 gr2, 9 gr1); no pts required a dose reduction after the second year of therapy. Bone fractures (fx) were reported in 4 pts (3 female/1 male) during the first 4 years of treatment (1 hip fx, 1 rib fx, 2 metatarsal stress fxs). Two of these 4 pts experienced a further fx approximately 1 year later (contralateral metatarsal; hip). Both pts with hip fx were > 10 years post-menopausal. Given median age at enrollment (34 years; range: 20-69 years) and reported fx events, bone health was evaluated with findings in keeping with expected range for age. No secondary malignancies have been identified to date. Conclusions: No patients receiving nirogacestat have progressed after a median of more than 4 years of treatment. The long duration of responses and lack of tumor progressions observed in this trial has informed the design of a phase III trial in pts with progressing desmoid tumors (NCT03785964) that is currently underway. Clinical trial information: NCT01981551.