Potential New Option in Aggressive, Ultra Rare Sarcoma

Treatment with an investigational albumin-bound mTOR inhibitor showed long-lasting responses in patients with advanced malignant perivascular epithelioid cell tumors (PEComa), extended follow-up from the single-arm AMPECT study showed.

On independent review, the overall response rate (ORR) with nab-sirolimus in 31 malignant PEComa patients was 39% (95% CI 22-58), including one complete response, meeting the primary endpoint, reported Andrew Wagner, MD, PhD, of Dana-Farber Cancer Institute in Boston.

With a minimum 18 months follow-up from the start of treatment, the median duration of response (DOR) was not reached, with rates of 92% at 6 months, and with two-thirds still in response at 12 and 18 months, he said at the Connective Tissue Oncology Society virtual meeting.

“Responses in AMPECT were highly durable, and 50% of patients had an ongoing response at over 25 months,” Wagner said, with no new safety signals observed.

An additional 52% of patients achieved stable disease, and the disease control rate (of at least 12 weeks) was 71%.

“The substantial response rate, durability of response, high rate of disease control, and manageable toxicities suggest that nab-sirolimus may represent an important new treatment option for this disease,” he concluded.

Biomarker analyses in the phase II study showed TSC2 mutations to be significantly associated with tumor response, with an ORR of 89% in this subgroup. In five patients with TSC1 mutations, one had a confirmed response.

“However, nab-sirolimus shows activity regardless of mutational status,” said Wagner, adding that seven of 12 responders remained on treatment, including one patient without TSC1/2 mutations.

Researchers also found that absence of S6 phosphorylation on immunohistochemistry staining was significantly associated with a lack of treatment response.

Median progression-free survival (PFS) in the cohort was 8.9 months and overall survival reached 40.8 months.

Malignant PEComa is an “ultra rare and aggressive” soft-tissue sarcoma that carries a high risk of metastases, explained Wagner, and no therapies are specifically approved for this indication.

Standard chemotherapies have only modest activity, but case reports and retrospective series have shown benefit with mTOR inhibitors such as sirolimus (Rapamune), everolimus (Afinitor), and temsirolimus (Torisel).

Wagner noted that “mTOR pathway activation is common in PEComa, typically through inactivating mutations of the TSC1 or TSC2 tumor suppressor genes.”

Nab-sirolimus (formerly ABI-009) is an albumin-bound form of sirolimus nanoparticles that has shown greater antitumor activity in preclinical studies compared with the orally administered forms, as well as increased intratumoral accumulation. The drug received breakthrough therapy designation from the FDA for malignant PEComa in 2019.

“What was very nice about these data is it actually tried to understand which patients are responding to ABI-009 and why,” said discussant William Tap, MD, of Memorial Sloan Kettering Cancer Center in New York City, who called the responses in AMPECT “dramatic.”

Tap pointed out that since this was a single-arm registration study with only 31 patients, a confirmatory trial will likely be in order, and suggested that such a trial should mirror the group that benefited most in AMPECT.

“Patients with TSC2 mutations have preferential responses,” said Tap. “In my mind, this clearly should inform usage and further clinical trial designs.”

In addition, he said, confirmatory trials should investigate the next series of scientific questions: Why are patients with TSC2 mutations more likely to respond, but not those with TSC1 mutations or tumors with abnormalities in p10 or PI3K? And why do some patients respond for long durations and what happens when they develop resistance?

“This may actually be able to inform how we use and study the drug moving forward,” he said.

Study Details

AMPECT was a prospective phase II study that evaluated nab-sirolimus in 31 patiens with malignant PEComa. Patients were eligible if they were ages 18 years or older and had an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1. The drug was administered intravenously at a weekly dose of 100 mg/m² for 2 weeks, followed by a week of rest, until disease progression or unacceptable toxicity.

Enrolled patients had a median age of 60 (71% white; 82% women) and three-fourths had an ECOG status of 0. Most had metastatic disease at presentation (85%), while the remaining had locally advanced, inoperable disease.

ORR was the primary endpoint. Investigator-assessed ORR was 42%, all of which were deemed partial responses, and investigator-assessed DOR rates were 85% at 6 months, 67% at 12 months, and 54% at 18 months.

Key secondary endpoints included DOR, PFS, and safety.

Wagner said the drug was well tolerated and that most treatment-related adverse events (AEs) were low grade and manageable, with 6% of patients stopping treatment for toxicity.

Common AEs (≥25%) included stomatitis/mucositis (79%), fatigue (59%), rash (56%), nausea (47%), anemia (47%), diarrhea (38%), weight decrease (38%), hyperglycemia (35%), thrombocytopenia (32%), hypertriglyceridemia (32%), hypercholesterolemia (32%), decreased appetite (32%), dermatitis (29%), dysgeusia (29%), headache (29%), and peripheral edema (26%). Additionally, pneumonitis occurred in 18%, said Wagner.

Grade 3 AEs included stomatitis/mucositis in 18%, anemia in 12%, hyperglycemia in 9%, and fatigue and thrombocytopenia in 3% each. No grade 4 AEs occurred and there were no treatment-related deaths.