James J. Harding, MD, describes the GI tumors where TSC1 or TSC2 alterations can arise, how the mechanism of action of nab-sirolimus may help fulfill an unmet need in this population, and the importance of using genetic testing to identify patients with mutations in TSC1, TSC2, or other genes to drive targeted treatment.
The mTOR inhibitor nab-sirolimus (ABI-009) may provide clinical benefit in patients with gastrointestinal (GI) cancers harboring TSC1 or TSC2 alterations, as these tumors depend on mTOR signaling, according to James J. Harding, MD.
The phase 2 PRECISION 1 basket trial (NCT05103358) is investigating nab-sirolimus in patients with malignant solid tumors, including GI cancers, with pathogenic inactivating TSC1 or TSC2 alterations in whom surgery is not an option or is likely to cause severe morbidity.1 Previously, the safety and efficacy of nab-sirolimus were evaluated in the phase 2 AMPECT trial (NCT02494570) in patients with advanced malignant perivascular epithelioid cell neoplasms (PEComas), in whom the agent produced an overall response rate of 39%.2 In PRECISION 1, patients will receive nab-sirolimus at the same dose and schedule as studied in AMPECT, 100 mg/m2 intravenously (IV) on days 1 and 8 of every 3-week cycle.
“mTOR activation in cancer has been known for a long time to be a critical driver of malignancy,” said Harding in an interview with OncLive®. “There’s a hypothesis that TSC1 and TSC2 alterations may be targetable with mTOR inhibition. The hypothesis has not yet been proven.”
In the interview, Harding described the GI tumors where TSC1 or TSC2 alterations can arise, how the mechanism of action of nab-sirolimus may help fulfill an unmet need in this population, and the importance of using genetic testing to identify patients with mutations in TSC1, TSC2, or other genes to drive targeted treatment.
Harding is an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.
Harding: TSC1 and TSC2 are tumor suppressor genes that are mutated in a subset of all solid tumors. They are found in 5% to 6% of GI cancers. Notable [GI cancer types that can harbor these mutations] include hepatobiliary cancers, small bowel ampullary cancers, and other tumors of the gut.
Beyond [TSC1 and TSC2 mutations], many solid tumors, including GI cancers, depend on mTOR signaling. It is a bit more challenging to identify those patients. Mutation-wise, [TSC1 and TSC2 mutations occur at a] lower frequency [than other mutations], but they do occur.
There isn’t a histology-agnostic approach. There has been a hypothesis for a long time that TSC1 and TSC2 loss would drive the mTOR pathway, and that precision medicine should have an effect there. Unfortunately, with the first-generation mTOR inhibitors, we have not seen that yet.
[However], there have been some hints. In PEComas, which are heavily dependent on mTOR signaling, there is anticancer activity when we target that pathway. [The potential for activity is] still unknown in the histology-agnostic TSC1 and TSC2 loss subset. That’s an unanswered question.
Nab-sirolimus is an mTOR inhibitor that’s different than first-generation mTOR inhibitors because it’s biochemically altered to be given through IV. This allows for higher exposure and more favorable pharmacokinetics. [This IV approach allowed for] more drug to be delivered to tumorous tissue in preclinical models.
Based on that, this agent was tested in a subset of patients with PEComas. These are rare soft-tissue sarcomas that are heavily dependent on mTOR signaling. In this prior phase 2 study, a high proportion of patients had a partial response. Based on that study, the FDA approved the drug in this rare histology.
The question becomes: If we select for patients with TSC1 or TSC2 loss using this novel, next-generation mTOR inhibitor, will we see more prominent tumoral shrinkage in this non-histology–dependent approach? This remains to be seen but is an important question.
Several reports in the literature from several cancers have suggested that tumors that are more dependent on mTOR signaling may be sensitive to mTOR inhibitors. This has been observed in kidney cancer, a subset of gynecologic malignancies, and hepatobiliary cancers like hepatocellular carcinoma. A prior basket study investigated any genomic alterations in the mTOR pathway that would drive [mTOR] signaling with everolimus [Afinitor]. This study didn’t show an overwhelmingly high response rate, [and there are many hypotheses as to why that was].
The current [PRECISION 1] proposal is to select loss of TSC1 or TSC2 and treat patients [with this loss] with nab-sirolimus, with the hypothesis that if a patient’s tumor is driven by this tumor suppressor, there would be resultant activity. This study is not based on a particular solid tumor; it’s dependent on having alterations in TSC1 or TSC2. This study seeks to enroll 120 patients with these alterations and treat them with nab-sirolimus at the dose that was used in the initial PEComa study, with a primary end point of objective response rate and several other key secondary end points.
For studies like this, we’re looking for patients with histologically confirmed solid tumors that have generally been exposed to prior SOC [standard of care] therapies. Patients will need to have the genomic classification or specific alterations in TSC1 or TSC2. Patients will also need to have a good ECOG performance status, have adequate organ function, and [meet other] standard entry criteria. The study is ongoing, and additional criteria can be found on ClinicalTrials.gov. It’s an exciting trial.
Genetic testing is critical in GI malignancies. It’s of critical importance in all solid tumors now. Specifically in GI cancers, several mutations are identified for which we have FDA approved drugs. [Regarding] immunotherapy, microsatellite instability–high or mismatch repair deficiency is notable in a small subset of cancers. There is a histology-agnostic approval for PD-1 inhibitors in this setting.
Beyond that, across solid tumors, HER2 overexpression or amplification is observed in gastric cancer, colon cancer, and biliary tract cancers. FDA-approved combinations target HER2 for gastric and colon cancer, and [approvals] will hopefully soon [happen for] hepatobiliary cancers as well. In addition, there are a subset of targetable MAP kinase pathway proteins, specifically BRAF V600E in colorectal cancer, and, to a lesser extent, in biliary cancers and others. The list goes on.
These are critical to define. [Genetic testing] helps us then determine how we treat patients in the metastatic setting, [as well as in] the adjuvant or perioperative settings in some instances. It’s truly critical now that we do this.
There is high-level evidence that nab-sirolimus is an active and safe drug, particularly in PECcomas. Now, we’re moving [this agent] to the precision medicine [field] as a basket study for solid tumors with TSC1 and TSC2 alterations to test the hypothesis that it may be active there. The study is now enrolling. If you identify patients with potential actionable alterations, referral to this trial is the appropriate thing to do to answer that question.
It’s an exciting time in oncology, particularly in precision medicine. In this way, we’ll have advancements for the patients, which is great.