Investigators Unpack Potential Role of Nab-Sirolimus for Solid Tumors With TSC1/2 Mutations

Brian Schulte, MD

The sirolimus albumin-bound nanoparticles for injectable suspension (nab-sirolimus; Fyarro) demonstrated strong efficacy signals for the treatment of sarcomas with TSC1/2 gene mutations and may expand its use to patients with nonresectable solid tumors in the PRECISION-1 trial (NCT05103358).¹

Data from the phase 2 AMPECT trial (NCT02494570) showed that among patients with perivascular epithelioid cell neoplasms (PEComas) who received nab-sirolimus (n = 31), durable responses were achieved and maintained. Patients had an overall response rate (ORR) of 39% (95% CI, 22%-58%) and updated data showed 2 complete and 10 partial responses. Median overall survival was 40.8 months (95% CI, 22.2 months–not reached) and 89% of patients with a TSC2 mutation experienced a confirmed ORR (P < .001).² The FDA approved the agent for these patients in November 2021.3

“We know from studies [such as] AMPECT, which was done for patients with PECcoma, targeting TSC1 and TSC2 or the mTOR pathway leads to a high response rate and a durable response for those patients,” Brian Schulte, MD, said in an interview with OncLive^®. “As part of an expanded access program that was done as part of the AMPECT trial, we did see a relatively high response rate [among a small] group of [patients with] heterogeneous [tumor types] that had failed an excess of 3 lines of treatment: over 50% of these patients had responded. What we found necessitated further study and our hope is that we’re going to be able to benefit a large group of patients by offering this therapy, but it is vital that we study and we answer this question further.”

Mark Agulnik, MD

“[PRECISION-1] will give us [more of] the information we’re looking for,” Mark Agulnik, MD, said in an interview with OncLive^®. “We’ll be able to see what patients are being enrolled, how the patients presented, what is the rate of [disease] growth is, etc, and we will be able to dissect a lot of information about the patients coming into the trial to have a better understanding of what is the true role of TSC1 and TSC2, and if we are able to impact outcomes by inhibiting these inactivating alterations.”

Schulte, an assistant professor of medicine at the University of California, San Francisco, and Agulnik, section chief of Sarcoma Medical Oncology in the Department of Medical Oncology & Therapeutics Research and a professor in the Department of Medical Oncology & Therapeutics Research at City of Hope in Duarte, California, further discussed the relevance of these mutations and actively enrolling phase 2 PRECISION-1 basket trial investigating the efficacy of nab-sirolimus in solid tumors.

OncLive^®: What is known about TSC1 and TSC2 mutations in solid tumors?

Schulte: TSC1 and TSC2 are pathogenic mutations that we see in a large variety of different histologies, histologic subtypes, [and] different malignancies and the prevalence varies depending on that type of cancer. This can be as frequent as approximately 8% in types of bladder cancer, approximately 5% in biliary cancers, 3.5% to 4% in endometrial cancers, [and] 3% of sarcomas in aggregate. It highly is dependent upon what type of cancer you’re looking at. Altogether, this encompasses thousands of patients across the country.

The TSC1 and TSC2 genes, are tumor suppressors by their nature. Their purpose is to abrogate proteins that are downstream, such as mTOR, which is the pathway they exist in. The thought is that by their mutation, [that] they’re not functioning anymore, those lead to further tumor growth through an alternate pathway.

What is known about the mTOR inhibitor nab-sirolimus? How could this agent potentially benefit patients with TSC1/2 mutations?

Schulte: Nab-sirolimus is an albumin-bound formulation of sirolimus. Sirolimus is a well-established medication; it’s commonly used for patients with hematologic malignancies for immunosuppression. In vitro and in vivo studies that were done with this formulation, the albumin-bound sirolimus, suggested that there were favorable pharmacokinetic and pharmacodynamic properties and this led to the impetus for the AMPECT trial.

Physicians who use this medication think of the administration [and] the adverse events [AEs] as being very comparable with those we see with other mTOR inhibitors. We see things such as mucositis, fatigue, anemia, and metabolic abnormalities, but it’s important to understand that although these [events] occur, there weren’t any grade 4/5 AEs on the AMPECT study. We would expect to see similar AEs in this patient population [in the PRECISION-1 trial].

Agulnik: Nab-sirolimus is an [intravenous] IV formulation, that is given at 100 mg/m2 twice every 3 weeks on days 1 and 8 of the 21-day cycle. If we look at some data with respect to nab-sirolimus vs sirolimus, what we know is that the concentrations in the blood are much higher with the nab-sirolimus formulation. What you could anticipate is that as you give this drug, more of the target is attacked and if you attack more of the target, you anticipate [a greater] treatment effect. That is the hypothesis behind this treatment, and why this drug has worked in PEComas. Now we anticipate the rollout for all patients with TSC1 and TSC2 mutations [in a clinical trial].

What’s nice is it is a phase 2 clinical trial, and we know the anticipated AEs and can counsel patients accordingly. There are no dose adjustments, and [participants] are given the FDA approved standard dosing [of nab-sirolimus]. That allows for patients to have a better understanding of their expected AEs.

Please describe the design of the phase 2 PRECISION-1 basket trial investigating nab-sirolimus in solid tumors harboring these mutations.

Schulte: PRECISION-1 is a phase 2 study with a primary end point of overall response, [specifically,] best overall response of the individuals who are receiving this treatment. There are 2 arms in this trial: arm A looking at TSC1 pathogenic mutations and arm B looking at TSC2 pathogenic mutations. We’re looking for a higher response rate than what one might otherwise expect in patients in this line of therapy.

Agulnik: This is a clinical trial that is looking to accrue 120 patients age 12 years or older, they should be naïve to mTOR inhibitors, have had a good ECOG performance status of 0 or 1, and the TSC1 or TSC2 inactivating alteration needs to be pathogenic and, therefore, it needs to be confirmed centrally because not all TSC1 or TSC2 abnormalities are inactivating alterations. This this must be [confirmed] from a next-generation sequencing report, or if there is some tissue DNA analysis done.

Patients must have measurable disease some measurable disease of [approximately] about 1 cm [in diameter] of tumor. Patients had to have had prior therapies, so this cannot be the first therapy that they’re going to undergo. All patients will be treated with active drug there is no placebo or randomization as part of this study.

Patients will be stratified by TSC1 and TSC2 mutations. Are there any anticipated outcomes for one being more favorable than the other?

Schulte: Based on the data that we have already [it’s difficult to say] whether there’s going to be a significant difference in outcomes or toxicity for these 2 groups. Remarking on what published data we do have, particularly the AMPECT study, we did see a nonstatistically significant improved response rate in patients with TSC2 alterations as opposed to TSC1. It’s important to recognize that this was a small number of patients and extrapolating from that to a different population of patients at a different point in their treatment would be unfair.

Agulnik: When we’re looking at numbers [in AMPECT] there were approximately 32 patients who were evaluable. [Any] number less than 35 becomes very hard to make conclusions. I’m anticipating that with 60 patients in each arm [in PRECISION-1] that will be able to finally make a conclusion after the 120 patients are enrolled in this study. From a patient perspective, I don't know that one should hope for a TSC1 or TSC2 alteration, because we don’t yet have the data.

Please discuss the anticipated patient population for enrollment.

Schulte: PRECISION-1 is enrolling patients who have advanced metastatic nonresectable solid tumors. [It is] vital to understand these patients have to have been failed already by accepted therapies for their solid tumors prior to enrolling, and that’s a discussion that would be had with the patient and the investigator to determine exactly what that means.

Agulnik: Any solid tumor will be eligible for this, and as we look at the number of patients who are potentially eligible with respect to who harbors this TSC1 or TSC2 alterations, we would anticipate [enrolling] patients from our [genitourinary] colleagues and from our [gastrointestinal] oncologists because there certainly should be patients with bladder, kidney, colon, stomach, esophageal cancers [with these mutations], but it is open to patients with melanoma and lung cancer, as well as the sarcomas.

The barrier to enrollment is going to be the same barrier we see when we’re trying to enroll any tissue agnostic trial: competing trials for [the same] malignancy. As a patient, do you enroll in a bladder cancer trial, or do you enroll in a tissue agnostic trial? We must make sure that all physicians within a group are knowledgeable that this trial exists so they could divert patients into these trials as these are very rare mutations. We’ve seen other situations where we try to enroll patients in agnostic tumor with rare genetic alterations trials and we have succeeded. There is no reason to suggest that we won’t succeed with this study as well, it will just take a little bit of time [to enroll].

References

1. Phase 2 basket trial of nab-sirolimus in patients with malignant solid tumors with pathogenic alterations in TSC1 or TSC2 genes (PRECISION 1). ClinicalTrials.gov. Updated December 22, 2022. Accessed January 25, 2023. https://clinicaltrials.gov/ct2/show/NCT05103358
2. Wagner AJ, Ravi V, Riedel RF, et al. nab-sirolimus for patients with malignant perivascular epithelioid cell tumors. J Clin Oncol. 2021;39(33):3660-3670. doi:10.1200/JCO.21.01728
3. FDA approves sirolimus protein-bound particles for malignant perivascular epithelioid cell tumor. FDA. Updated November 23, 2021. Accessed January 25, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sirolimus-protein-bound-particles-malignant-perivascular-epithelioid-cell-tumor