Malignant Perivascular Epithelioid
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Intravenous sirolimus (albumin bound, SRL-HSA) was well tolerated and elicited durable responses in patients with malignant perivascular epithelioid cell tumors (PEComa), according to findings from a phase 1b trial (NCT05625919) presented during the 2025 ESMO Sarcoma and Rare Cancers Congress.1

At a data cutoff date of December 9, 2024, and with a median follow-up of 9.9 months, SRL-HSA elicited an objective response rate (ORR) of 34.1% (95% CI, 20.1%-50.6%) in all evaluable patients (n = 41). When broken down further, 2.4%, 31.7%, 31.7%, and 24.4% of patients achieved complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), as their best overall response (BOR); 9.8% were not evaluable (NE). The disease control rate (DCR) was 65.9% (95% CI, 49.4%-79.9%).

In a subset of patients without previous exposure to mTOR inhibition (n = 34), the ORR achieved with SRL-HSA was higher, at 41.2% (95% CI, 24.7%-59.3%). BORs included CR (2.9%), PR (38.2%), SD (26.5%), and PD (20.6%); 11.8% of patients were NE. In this group, the DCR was 67.7% (95% CI, 49.5%-82.6%).

In terms of safety, no patients discontinued treatment with SRL-HAS or experienced treatment-related adverse effects (TRAEs) that proved fatal. The most common grade 3 or higher TRAE experienced with this approach was hypertriglyceridemia, and this was reported in 11.4% of patients. The recommended phase 3 dose (RP3D) was established to be 100 mg/m2.

“These data support phase 3 study to further explore the efficacy of SRL-HSA in patients with malignant PEComa,” Xiaohui Niu, MD, director of the Department of Orthopaedic Oncology Surgery at Beijing Jishuitan Hospital, in China, said in a presentation of the data.

Delving Into the Phase 2 Trial: Design, Treatment, Objectives, Population

The open-label, 2-part, multicenter phase 2 trial enrolled patients with histologically confirmed advanced soft tissue sarcoma, which included malignant PEComa for part 1 of the trial and recurrent or metastatic malignant PEComa without prior exposure to mTOR inhibition for part 2. All patients were required to be at least 18 years of age, have 1 or more measurable lesions per RECIST 1.1, and an ECOG performance status no higher than 1.

Part 1 of the trial, or the dose-escalation and pharmacokinetic expansion portion, utilized a rolling-six design. SRL-HSA was tested at 50 mg/m2 (n = 3), 85 mg/m2 (n = 6), and 100 mg/m2 (n = 17); it was given intravenously on days 1 and 8 of 21-day treatment cycles. No dose-limiting toxicities (DLTs) occurred, and 100 mg/m2 (n = 18) was identified for evaluation in part 2, or the dose expansion portion, of the research.

Safety and RP3D served as the trial’s primary end points for part 1, and ORR served as the primary end point for part 2.

In all 44 patients, the median age was 50.5 years (range, 23-71), and the majority were female (n = 29). Most had an ECOG performance status of 1 (61.4%), a clinical diagnosis of advanced malignant PEComa (95.5%), and metastasis (81.8%). Moreover, 27.3% of patients had at least 3 metastatic sites and 22.7% had liver metastasis. Additionally, 15.9% of patients had received prior mTOR treatment.

Additional Efficacy Data Revelations

The median time to response (TTR) was 1.51 months (interquartile range [IQR], 1.35-2.79) and median duration of response (DOR) was not reached (NR). The 3-, 6-, 9-, 12-, and 15-month DOR rates were all 100% (95% CI, 100%-100%). The median progression-free survival (PFS) was NR (95% CI, 3.9-NR); the 3-, 6-, 9-, and 12-month PFS rates were 70.7% (95% CI, 53.4%-82.6%), 60.8% (95% CI, 42.5%-74.9%), 60.8% (95% CI, 42.5%-74.9%), and 60.8% (95% CI, 42.5%-74.9%), respectively.

In the subset of patients without exposure to prior mTOR inhibitors, the median TTR was also 1.51 months (IQR, 1.35-2.79), the median DOR was NR, and the 3-, 6-, 9-, 12-, and 15-month DOR rates were all 100% (95% CI, 100%-100%). The median PFS in this group was also NR (95% CI, 5.7-NR), with a 3-month PFS rate of 73.7% (95% CI, 54.2%-85.9%). The 6-, 9-, and 12-month PFS rates were all 65.4% (95% CI, 44.7%-79.9%).

Safety Spotlight

In all patients, 95.5% of patients experienced treatment-emergent AEs (TEAEs) with 34.1% of cases grade 3 or higher. TEAEs resulted in dose interruption, reduction, and discontinuation for 45.5%, 6.8%, and 2.3% of patients, respectively. One patient experienced TEAEs that proved fatal. TRAEs occurred in 95.5% of patients with 31.8% of cases being grade 3 or higher. TRAEs led to dose reduction for 6.8% of patients and interruption for 45.5% of patients. Notably, serious TRAEs occurred in 13.6% of patients.

The most common TRAEs experienced by at least 20% of patients included oral mucositis (all grade, 54.5%; grade ≥3, 4.5%), increased alanine aminotransferase levels (47.7%; 2.3%), increased aspartate aminotransferase levels (45.5%; 2.3%), anemia (45.5%; 2.3%), hypercholesterolemia (43.2%; 4.5%), hypertriglyceridemia (43.2%; 11.4%), decreased white blood cell count (36.4%; 0%), hyperglycemia (36.4%; 0%), rash (36.4%; 0%), decreased neutrophil count (29.5%; 0%), decreased platelet count (27.3%; 2.3%), proteinuria (27.3%; 0%), weight loss (25.0%; 0%), hypokalemia (20.5%; 2.3%), and oral ulter (20.5%; 0%).

Disclosures: None.

Reference

Niu X, Zhang X, Guo J, et al. 66MO Intravenous sirolimus (albumin bound, SRL-HSA) in malignant perivascular epithelioid cell tumors (PEComas): A multicenter, open label, phase Ib trial. ESMO Open. 2025;10(suppl 3):104380. doi:10.1016/j.esmoop.2025.104380