Exploring the Benefits of Nab-Sirolimus in Advanced PEComa Treatment

Jacob Stein, MD, MPH

With rare cancers like perivascular epithelioid cell tumors (PEComa), precision medicine, molecular testing, and multidisciplinary care are critical for accurate diagnosis and effective treatment.

Nab-sirolimus (Fyarro) is an mTOR inhibitor that has shown promising outcomes for patients with advanced PEComa, particularly compared with traditional chemotherapy and tyrosine kinase inhibitors, which have low response rates. The agent was granted approval from the FDA in 2021 treatment of patients with advanced malignant PEComa.¹

In the AMPECT trial (NCT02494570), nab-sirolimus showed an objective response rate of 39% (95% CI, 22%-58%), with a median progression-free survival of 10.6 months (95% CI, 5.5-41.2), and an overall survival of 53.1 months (95% CI, 22.2 to not reached).² According to Jacob Stein, MD, MPH, the agent does not require biomarker testing for treatment eligibility, allowing broader access for patients, though certain mutations like TSC-2 may correlate with better responses.

Safety data for nab-sirolimus has shown adverse events to be generally mild, with low discontinuation rates due to toxicity. Monitoring involves imaging every 3 months, while management of adverse effects like mucositis includes good oral hygiene practices and supportive care.

In an interview with Targeted Oncology^TM, Stein, assistant professor of medicine at the University of North Carolina at Chapel Hill, lead of the Sarcoma Medical Oncology Section, discussed nab-sirolimus and its impact on patients with advanced PEComa.

Photorealistic illustration of sarcoma - Generated with Google Gemini AI

Targeted Oncology: How does nab-sirolimus improve outcomes for patients with advanced PEComa compared with other treatments or no treatment options?

To start with a little bit of orientation of PEComa, these are ultra rare mesenchymal tumors. The incidence is about one in a million, and they are related to some other benign diseases, like angiomyolipoma, but these malignant PEComas can arise in a retroperitoneum. They can arise in the uterus, and for most of the time clinical practice, if it is an isolated lesion, the answer is resection, and [patients] do not need adjuvant therapy or anything else, and they have a pretty good chance of cure. But if they come back, they can be quite problematic.

Chemotherapy does not tend to work well in this disease. This is a rare tumor, which means we do not have the highest quality data on this, but studies tend to show a response rate of about 10% to 20% and a progression-free survival in the 3-month range with typical chemotherapy, which is pretty poor. Tyrosine kinase inhibitors have been explored, but similarly, have pretty poor response rates and PFS in the maybe 5- or 6-month range.

We know that PEComas are driven by mTOR activation, and that is what led to the interest in nab-sirolimus. This was shown to have benefit in the AMPECT trial, which was a national, multicenter study. They enrolled 31 patients, which does not sound like that much, but again, when we are talking about a super rare disease, that is a fantastic success. They showed impressive results with this drug. The objective response rate was nearly 40%, median PFS was 10.6 months, and overall survival was over 40 months – that’s over 3 and a half years.

Why is nab-sirolimus effective for PEComa without requiring biomarker testing? How does that influence treatment decisions?

I appreciate the way that they did the study, which is that they did not require biomarker testing for eligibility or entry. From my standpoint as a clinician, I feel comfortable offering it to patients regardless of biomarker testing and entry. [I think] molecular testing and [next-generation sequencing (NGS)] are needed. It is an important part of the diagnostic process for these [patients]. But even if it is still pending or you were not able to get NGS, these are patients you still can treat with nab-sirolimus and feel that you have a good chance of getting a response. When we look back at the study to see how biomarkers influenced outcomes, we do see that certain genetic profiles led to better responses. Patients with TSC-2 had the most impressive and long-lasting responses. But there were [patients] with TSC-1 and those without either mutation that had nice clinical benefits. Certainly, this is a drug you can offer regardless of the molecular profile.

What is your approach to monitoring patients with PEComa on nab-sirolimus who do not show specific mutations?

My approach does not really change in terms of monitoring. Certainly there are [patients] who may not respond, but that is true, essentially, with any of these ultra rare diseases. I do imaging every 3 months, and maintain an index of suspicion to re-image sooner if somebody has new symptoms or is not doing well. But essentially, I am following all these [patients] with close imaging surveillance.

What makes the agent's safety data so significant for PEComa treatment?

That is a part of what is so appealing about this drug. A lot of the therapies that we use in sarcoma are cytotoxic chemotherapy agents, and this is not, thus the tolerability is much better. In the original study, only about 5% of patients had to stop therapy due to an adverse event, which is a pretty low number overall. The vast majority of adverse events that we saw were grade 1 and 2, so again, pretty tolerable.

What strategies do you recommend for managing mucositis in patients treated with nab-sirolimus?

Mucositis is the most common [adverse event] that we see, which is not surprising given its known association with mTOR inhibitors. In the study, 80% of patients experienced mucositis; however, only about 18% had grade 3 toxicity, which affects their ability to eat or drink.

In clinical practice, we manage this by recommending baking soda rinses and dexamethasone mouthwash prophylactically, to address the issue before it arises. We emphasize good oral hygiene and provide behavioral tips, such as avoiding spicy foods, alcohol, and certain mouthwashes. These small recommendations can significantly help patients. I would also highlight that a multidisciplinary team can greatly support patient care. Nurses, patient navigators, and pharmacists can be invaluable in helping patients navigate these types of [adverse events].

What other adverse events should oncologists be prepared for? How can they be managed?

There are a variety of metabolic things that we can see, [including] elevated blood sugars and elevated lipid levels. Those do not tend to be a big deal. Sometimes we will see mild anemia or a little bit of fatigue, but again, not typically things that dramatically affect quality of life. One other adverse [event] that is important to talk about is pneumonitis. There is a real risk of pneumonitis with this drug; it was seen in about 30% of patients in the study. That is potentially significant. There were a couple of reassuring things when I look at the trial data, which is that the vast majority of pneumonitis events were grade 1 or 2, 95% completely resolved, and no one had to come off the drug because of pneumonitis on the trial. Those suggest that this is manageable and does not tend to be a severe or long-lasting issue. I was speaking with a clinical partner recently who was asking about doing anticipatory imaging for this, and I do not recommend routine hi-res surveillance CTs. It is just important to maintain an index of suspicion and some vigilance, so that if somebody says they are having new shortness of breath or a new cough, think of pneumonitis and get the imaging at that point.

Why is PEComa often misdiagnosed? What can clinicians do to improve diagnostic accuracy?

This is a challenge in sarcoma generally. The main reason is that it is a super rare disease, and so even an excellent pathologist is only going to see a handful of these in a year if they do not have a specific focus in sarcoma. There is also a lot of overlap with other sarcomas. This can particularly happen in the uterus, and so there can be overlap between leiomyosarcoma or endometrial stromal sarcoma, and the staining pattern is not always clear cut. These can be really tricky cases.

I would emphasize 2 important points. First, patients need to be seen at a referral center to ensure access to expert pathology and clinicians familiar with the disease and treatment options. I recommend that all patients, even if they plan to receive treatment in the community, have at least an evaluation at a referral center.

Second, as I mentioned earlier, the importance of next-generation sequencing cannot be overstated. We should be sending sequencing for these patients 100% of the time because the molecular profile can aid in diagnosis and help distinguish between different entities. For example, in PEComa, the TSC mutation often clarifies the diagnosis, while for other sarcomas, identifying a specific fusion gene product can lead to a different diagnosis. This molecular profiling is a key element in accurate diagnosis.

How important is histopathology and identifying PEComa? What should oncologists focus on?

It is super important. Again, the biggest thing would be that you want these cases reviewed by somebody with sarcoma-specific expertise. Whether they get sent to Mayo Clinic or an academic center near you, they need that second opinion to ensure the diagnosis is right.

Are there any promising trials that could expand treatment options for patients moving forward?

There are a variety of promising areas of active research. Immunotherapy is potentially effective. I personally have had some [patients] that I have treated with excellent response rates and durable responses. It is not effective for everyone, and so we need to better understand, either using biomarkers or other approaches, to figure out who are the [patients] that are going to benefit from immunotherapy. Other important questions are, should we be adding combination therapy to nab-sirolimus or other mTOR inhibitors? Should we be adding second agents at time of progression? Do we need more potent mTOR inhibitors? Are there other pathways that we need to be targeting in this disease? Those are the key questions that the field is continuing to research.

How do you see precision oncology advancing treatment for rare cancers like PEComa?

I think precision oncology is absolutely critical in the field of sarcoma. This group of diseases has made significant progress over the past couple of decades, particularly in diagnosis and understanding the heterogeneity within these diseases, and precision medicine plays a major role in that advancement. My recommendation is to perform next-generation sequencing for essentially every newly diagnosed sarcoma, including PEComa, as it can provide substantial benefits for individual patients.

Identifying one of these fusion genes can confirm a diagnosis for a specific sarcoma subtype. Additionally, targeted therapy can sometimes be effective; if we discover mutations such as ROS or NTRK, we have the potential to significantly alter a patient's disease trajectory. However, the bigger picture is the routine and systematic collection of sequencing data in a structured manner, allowing us to better understand disease patterns and identify new treatment pathways. This approach represents the path forward in sarcoma, and it is an exciting time for the field.

REFERENCES:

1. Aadi Bioscience announces FDA approval of its first product FYARRO™ for patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa). News release. Aadi Bioscience. November 23, 2021. Accessed October 23, 2024. https://bit.ly/3oNbzMg

2. Wagner AJ, Ravi V, Riedel RF, et al. Phase II trial of nab-sirolimus in patients with advanced malignant perivascular epithelioid cell tumors (AMPECT): Long-term efficacy and safety update. J Clin Oncol. 2024;42(13):1472-1476. doi:10.1200/JCO.23.02266