(P 156) MANAGEMENT OF ADVERSE EVENTS IN THE AMPECT TRIAL OF NAB-SIROLIMUS FOR THE TREATMENT OF ADVANCED MALIGNANT PECOMA

Objective: nab-Sirolimus is a mechanistic target of rapamycin inhibitor (mTORi) that utilizes albumin-bound nanoparticle technology. In preclinical animal models, treatment with nab-sirolimus resulted in significantly higher tumor uptake, mTOR target suppression, and tumor suppression, with a distinct pharmacokinetic profile, relative to oral mTORis. nab-Sirolimus is approved in the US for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa) based on the primary analysis results of the AMPECT trial, performed 6 months after the last patient enrolled (Wagner et al. J Clin Oncol. 2021). Here, we describe adverse event (AE) management in AMPECT through 2 years after the primary analysis.

Methods: The AMPECT trial was an open-label, multicenter Phase 2 registration study in mTOR-naïve adult patients (age ≥18 years) with a histologically confirmed diagnosis of malignant PEComa and Eastern Cooperative Oncology performance status score of ≤1. Patients received nab-sirolimus 100 mg/m2 intravenously on Days 1 and 8 of a 21-day cycle. Two dose reductions to 75 and 56 mg/m2 were permitted for toxicity. Treatment was continued until unacceptable toxicity, disease progression, or patient preference for withdrawal. Dosing was reduced for hematologic and other toxicities. If a clinically significant AE occurred, treatment could be withheld and supportive therapy administered, as clinically indicated; dose reduction of nab-sirolimus was to be considered if clinically indicated. If the AE resolved to Grade 1 or baseline at the reduced dose level, the dose could be increased to the previous dose level.

Results: All 34 treated patients experienced at least 1 treatment-related AE (TRAE), including 8 patients with serious TRAEs and 2 discontinuations due to TRAEs. Pre-identified AEs of special interest included stomatitis and pneumonitis, which occurred in 24/34 and 6/34 patients, respectively. Pneumonitis and mucositis were managed through dose modifications and/or concomitant medications. One-third of mucositis events (36%) and 23% of pneumonitis events resolved without intervention. The majority of pneumonitis events (77%) and stomatitis events (64%) were successfully managed with drug interruptions and/or concomitant medications; stomatitis was most commonly managed with steroid mouthwash, and 59% of all patients received stomatological preparations (most frequently magic mouthwash, sucralfate, nystatin, and dexamethasone).
Of the 31 efficacy-evaluable patients, 14 had at least 1 dose reduction and 2 patients received 2 dose reductions during the study. Most dose reductions (12/16) occurred within the first 3 months of treatment. The most frequent AEs leading to dose reduction were pneumonitis (4/16) and stomatitis (3/16); others included alanine transferase (ALT)/aspartate transferase (AST) elevations, acute coronary syndrome, abdominal pain, hyperglycemia, thrombocytopenia, increased creatinine, dehydration, and fatigue, all in 1 patient each. All 16 AEs resolved to grade 0 after dose modifications, except for grade 1 AST elevation in a single patient, which was ongoing at the data cutoff. Five of 14 patients with a dose reduction had a confirmed response; all 5 maintained their response for 6 to 36 months after dose reduction. Two patients with dose reductions at 38.5 and 18.5 months remained on nab-sirolimus as of June 30, 2021 with a partial response, and 1 patient with dose reduction at 2.1 months converted to a complete response at 33.9 months.

Conclusion: AEs due to nab-sirolimus treatment in the AMPECT trial were manageable, and dose reductions for AE management did not appear to compromise efficacy.