Iyer Shares Ongoing Research in TSC1/2-Mutant Genitourinary Cancers

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Gopa Iyer, MD, explained the rarity of TSC1 and TSC2 mutations in GU cancers, discussed the rationale and design of PRECISION 1, and emphasized the important role next-generation sequencing plays when determining the most effective targeted therapies for patients with GU cancers and other tumor types.

Gopa Iyer, MD

Gopa Iyer, MD

For patients with TSC1- or TSC2-mutated genitourinary (GU) cancers such as bladder and kidney cancer, the mTOR inhibitor nab-sirolimus (ABI-009) could join the treatment landscape as a safe and effective targeted therapy, according to Gopa Iyer, MD.

The efficacy and safety of nab-sirolimus monotherapy are being evaluated in the phase 2 PRECISION 1 trial (NCT05103358), a basket study that is currently enrolling patients with malignant solid tumors harboring pathogenic inactivating TSC1 or TSC2 alterations.1

“Because this is an albumin-bound compound, the hope is that it’ll be better tolerated and more effective than some of the other traditional rapalogs like everolimus [Afinitor] and temsirolimus,” Iyer said.

In an interview with OncLive®, Iyer explained the rarity of TSC1 and TSC2 mutations in GU cancers, discussed the rationale and design of PRECISION 1, and emphasized the important role next-generation sequencing (NGS) plays when determining the most effective targeted therapies for patients with GU cancers and other tumor types.

Iyer is the section head of bladder cancer at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive®: How prevalent are TSC1 and TSC2 mutations in GU cancers?

Iyer: In general, they are not common across any cancer type. [Based on] some of the larger genetic datasets in bladder and kidney cancer, TSC1 and TSC2 inactivating alterations are in anywhere between 1% to 5% of those tumors. Prostate cancer also has TSC2 mutations in less than 0.5% of tumors. [These mutations are] less frequent than some other drivers, but they do exist, and they’re present across many other cancer types as well.

Given the rarity of TSC1 and TSC2 alterations, what unmet needs exist for patients with tumors harboring these mutations?

Standard-of-care [SOC] treatments exist for all these patients across cancer types. However, at some point, unfortunately, most patients with these tumors will progress. Having a targeted agent that can specifically inhibit 1 pathway is still appealing. Although the incidence of TSC1 and TSC2 alterations is rare in any given tumor type, from a tumor-agnostic standpoint, [you can treat] a meaningful number of patients with this drug.

One agent under investigation in tumors with these mutations is nab-sirolimus. What is currently known about this agent, and what is the rationale for investigating it in these tumors?

Nab-sirolimus was FDA approved in 2021 for adult patients with unresectable or metastatic, malignant perivascular epithelioid cell tumor [PEComa], a rare type of sarcoma. This was based on findings from the [phase 2] AMPECT trial [NCT02494570], which showed an overall response rate of 39%.

An exploratory analysis was subsequently performed, in which genetic sequencing of the patients who were enrolled in this trial found that TSC2 inactivating alterations were associated with responses, with 89% of patients, or 8 of 9 patients, with a TSC2 inactivating alteration having a confirmed response and 1 patient having an unconfirmed response. Potentially, all these patients had a partial response [PR] to therapy.

Some patients also had TSC1 inactivating alterations, with a 20%, PR rate, or 1 of 5 patients having a response to therapy. [Of the 4 patients with TSC1 mutations who did not respond, 2 had stable disease (SD) for at least 12 weeks].

A subsequent expanded access program of nab-sirolimus was performed across tumor types that showed encouraging preliminary results in patients with advanced solid tumors. One patient with endometrial cancer, [patients with sarcomas such as] leiomyosarcoma, and patients with ovarian cancer had PRs to treatment. [Additionally, patients with angiosarcoma achieved SD with the agent]. This was encouraging and led to the PRECISION 1 trial.

Nab-sirolimus is sirolimus, which is a rapamycin, or an inhibitor of mTOR, bound to albumin. The idea is that this albumin-bound sirolimus will be better able to enter tumors and will have higher penetration and higher accumulation through an albumin receptor–mediated entry. Because of that, we may see improved activity compared with some of the other rapalogs, like everolimus.

How is the PRECISION 1 trial designed?

This is a prospective phase 2 open-label study. It’s a multi-institutional basket trial investigating the efficacy and safety profile of nab-sirolimus. Any patient, including some pediatric patients, 12 years of age or older is eligible for the study. They cannot have had prior mTOR inhibitors. If they have a confirmed TSC1 or TSC2 pathogenic inactivating alteration, they are potentially eligible.

One nice aspect of the study is that [mutation status] can be evaluated by NGS of any tumor tissue–derived DNA and can be done using any platform. Ultimately, [mutation status] is centrally confirmed through a review of the NGS data to confirm a pathogenic inactivating alteration. [This trial] doesn’t require a second testing or a repeat biopsy. If patients have measurable disease and have failed prior treatments, they are potentially eligible.

All patients will receive nab-sirolimus at the dose that was approved by the FDA, 100 mg/m2, given intravenously. One cycle is 21 days, and patients receive treatment once weekly for 2 weeks out of 3.

[This trial will have] 2 arms. One arm includes patients with pathogenic inactivating TSC1 alterations and the other pathogenic inactivating TSC2 alterations. [This trial aims to enroll] 60 patients per arm. Patients will remain on the study until evidence of progression of disease or intolerance to treatment.

[This trial is] specifically based upon the data we have so far from the AMPECT study, the expanded access program, and some extreme responder results that have been published over the past decade across different cancer types where patients who had TSC1 or TSC2 alterations experienced prolonged benefit from rapalog therapy. [That research has informed] the rationale to study nab-sirolimus in this specific patient population.

What are the challenges of enrolling patients to this trial, and how can these obstacles be addressed to increase enrollment?

An issue with many current basket trials that are investigating rare genetic mutations across tumor types [is that we need to] encourage providers to do NGS as frequently as possible because they may unearth a TSC1 or TSC2 alteration and provide an added treatment option for patients.

Another way to improve enrollment is through expanded outreach. [We need] to allow community oncologists, as well as academic sites, to know about the study and state the different institutions around the country that have this study open, making it easy for patients to access the trial at those institutions. Word of mouth is going to be huge, and encouraging NGS as much as possible is another way to try to expand access to patients. Once we hopefully start to see some preliminary efficacy data, [we also need to] make sure those are reported as early as possible.

What is the importance of performing NGS and genetic testing when patients are first diagnosed with cancers that may harbor TSC1 or TSC2 mutations?

It varies from cancer to cancer, but certainly in cancers like lung cancer or bladder cancer where an FDA-approved targeted therapy is already available, [such as the several approved] for lung cancer and everolimus for bladder cancer, we usually encourage doing up-front NGS as early as possible. This can be in patients who have organ-confined disease and certainly in first-line metastatic disease, because it takes time to get those results back and see that [certain agents] are options for patients.

Additionally, if we do genetic sequencing later in the patient’s treatment course, [enrolling these patients to studies] may be harder because unfortunately, patients’ performance statuses are not going to be as good after they’ve received and progressed on multiple lines of treatment. We may have limited time to identify a targetable genetic alteration and find a study for it.

[Conveniently], most NGS reports nowadays list specific clinical trials that are pertinent based upon the genetic profile of the tumor, including this nab-sirolimus study for any patients with TSC1 or TSC2 alterations. That will be helpful. Anything we can do to trigger this trial in the minds of treating oncologists will help get patients on this study.

What other ongoing research in GU cancers are you interested in?

In bladder cancer, specifically, a ton of exciting research is going on right now. From a targeted therapy standpoint, some newer FGFR3-specific inhibitors are going to be in clinical trials shortly, which is exciting. Erdafitinib [Balversa] is our only FGFR-targeted therapy in bladder cancer, but its toxicities can be difficult to tolerate in many patients. Some of these other isoform-specific inhibitors may be able to circumvent that.

[Additionally], HER2-directed antibody-drug conjugate therapies are gaining much excitement in this disease. It’ll be interesting to see how they do both as monotherapies and combined with immunotherapy.

What is your main message for colleagues regarding nab-sirolimus and PRECISION 1?

[In PRECISION 1], this drug should be [investigated] in tumors like renal cell carcinoma, where we already have FDA-approved rapalogs and where it might be worth trying this drug prior to those SOC options to see if we can get a better response and better tolerability.

Additionally, test early and often with NGS to identify these rare alterations for which there may be effective drugs available.


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 9, 2023. https://clinicaltrials.gov/ct2/show/NCT05103358

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