Recently, the FDA granted approval to nanoparticle albumin-bound sirolimus (nab-sirolimus) for the treatment of patients with metastatic malignant perivascular epithelioid cell tumor (PEComa). Dr. Richard F. Riedel, Associate Professor of Medicine at Duke University, was one of the investigators of the AMPECT study, on which the approval was based. In this interview, Dr. Riedel speaks with Oncology Data Advisor about the significance of the approval of nab-sirolimus for the treatment of patients with this rare disease.
Oncology Data Advisor: What is the typical prognosis for patients diagnosed with metastatic malignant perivascular epithelioid cell tumor?
Richard F. Riedel, MD: As is true for many cancers, PEComa included, the prognosis for patients with metastatic disease is poor. PEComa is considered an ultra-rare subtype of soft tissue sarcoma. Until recently, there were no FDA-approved agents. Historically, we would extrapolate data from more common sarcoma subtypes and use conventional cytotoxic chemotherapeutic agents in PEComa. Unfortunately, we learned very quickly that the response rates to these therapies were very low, and it became clear that novel therapies were needed.
Oncology Data Advisor: That's good to know, and it really does show how significant the recent FDA approval was. Thank you for that. So how does nab-sirolimus change the outcomes for patients with metastatic malignant perivascular epithelioid cell tumor?
Dr. Riedel: The rationale for the use of mTOR inhibitors, such as nab-sirolimus, is based on the finding that PEComa can exhibit activation of the mTOR pathway. This can be mediated, in some cases, through specific mutations in TSC1 or TSC2. The initial activity of mTOR inhibitors in PEComa was reported in case reports and small case series.
What is unique about nab-sirolimus is that it's administered intravenously and designed to have better bioavailability compared with orally available agents. One of the challenges with oral therapies is that they need to be absorbed from the gut into the bloodstream, where there can be variable absorption. In addition, monitoring of drug levels is often required. By administering the therapy intravenously, you avoid that variable absorption and there is no need for drug monitoring. Preclinical data has shown that this novel intravenous formulation—nab-sirolimus—has improved efficacy when compared with some of the oral inhibitors.
Oncology Data Advisor: Well, that's really helpful to know. Are there any particular adverse events that should be monitored for in patients receiving nab-sirolimus?
Dr. Riedel: There are some side effects of mTOR inhibitors, in general, that are common to the entire class of agents. These include effects on the bone marrow, specifically the potential for anemia, thrombocytopenia, and neutropenia, as well as mucositis, nausea, fatigue, rash, diarrhea, and effects on the lipid panel. These effects are seen with commercially available mTOR inhibitors, as well as nab-sirolimus. It is worth mentioning that in the AMPECT study, no new significant side effects were observed.
Oncology Data Advisor: What are the future directions in the treatment of metastatic malignant PEComa?
Dr. Riedel: That is a great question and certainly a challenging one when dealing with an ultra-rare disease like PEComa. The AMPECT study was a registrational single-arm phase 2 study enrolling only 34 patients. The study resulted in FDA approval based on a very encouraging response rate of 39% in patients with advanced disease. The median progression-free survival was 10.6 months, and the median overall survival was 40.8 months. I think future directions could involve consideration for novel combination approaches, potentially with antiangiogenic or immunotherapeutic therapies.I also think identification of novel biomarkers to predict response to therapy would be important. Of note, in the AMPECT study, patients enrolled with a mutation in TSC2 had an overall response rate of 89%. This is very intriguing and requires additional investigation, as the number of patients in this cohort was small.
Oncology Data Advisor: What is your advice to community oncologists treating patients with metastatic malignant PEComa?
Dr. Riedel: I think it is critically important that patients with metastatic malignant PEComa be referred to centers with expertise. The management of these patients often requires a multidisciplinary approach, and the care for each patients needs to be individualized. Confirmation of the diagnosis is also critical and requires a pathologist with expertise in soft tissue sarcoma. I would strongly encourage and recommend that community oncologists partner with their academic sarcoma colleagues in order to provide the best care for their patients.
About Dr. Riedel
Richard F. Riedel, MD, is an Associate Professor with Tenure in the Division of Medical Oncology at Duke University Medical Center. Additionally, he serves as the Associate Director of Clinical and Translational Research for the Duke Sarcoma Program and is a member of the Duke Cancer Institute. His clinical practice is dedicated to the care of patients with bone and soft tissue sarcoma, and his research interests lie in identifying novel therapies for these patients. Dr. Riedel is a nationally recognized expert in the field of soft tissue and bone sarcoma and is active at the national level in preparing national sarcoma guidelines (NCCN Soft Tissue Sarcoma Guidelines panel member and NCCN GIST Guidelines panel member) and educational initiatives. He has authored or coauthored numerous peer-reviewed publications focused on improving outcomes for patients with sarcoma through novel therapies.
For More Information
J Clin Oncol, 39(33):3660-3670. DOI:10.1200/JCO.21.01728. Nab-sirolimus for patients with malignant perivascular epithelioid cell tumors.
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.