Dual mTORC1/mTORC2 Inhibitor Sapanisertib Shows Promise in Combination Regimens for Solid Tumors

Targeting the mTOR pathway with dual inhibitors of mTORC1 and mTORC2 such as sapanisertib (CB-228) can be effective for the treatment of patients with solid tumors when the mTOR inhibitor is used as a component of a combination regimen, according to Vivek Subbiah, MD.

When sapanisertib was combined with the antidiabetic agent metformin in a phase 1 study (NCT03017833), 79% of response-evaluable patients with locally advanced or metastatic solid tumors (n = 19/24) achieved disease control. Additionally, 17% of patients achieved a partial response (PR) and of 3 of the 4 patients with a PR had PTEN mutations; 2 of the 4 patients with a response also had comutations.¹ Findings from another phase 1 study (NCT02159989) showed that response-evaluable patients who received sapanisertib plus ziv-aflibercept (n = 50) experienced a disease-control rate (DCR) of 78%; 74% of patients experienced stable disease (SD) and 2 patients achieved a PR.²

“Drug development in the mTORC1/2 space has been challenging,” Subbiah said. “[Sapanisertib] and multiple other drugs have been tested in patients in a non-biomarker driven fashion. These 2 combination studies have clearly shown that mTORC1/2 inhibitors such as sapanisertib in combination [regimens] have activity in patients who harbor specific alterations. The next step should be to use these mTORC1/2 inhibitors in combination [with other agents] in specific biomarker driven and targeted populations.”

In an interview with OncLive®, Subbiah, chief of early-phase drug development at Sarah Cannon Research Institute in Nashville, Tennessee, detailed the rationale for combining sapanisertib with ziv-aflibercept and metformin, as well as the next steps for the development of mTOR inhibitors in solid tumors.

OncLive: What was the rationale for combining sapanisertib with ziv-aflibercept in patients with recurrent metastatic solid tumors and what key data were observed in the phase 1 study?

Subbiah: mTOR pathway inhibition with VEGFR inhibition has shown synergism in kidney cancer in many preclinical models, [and several] studies of mTOR inhibitors combined with VEGF inhibitors have demonstrated activity in multiple solid tumors. Ziv-aflibercept is a recombinant fusion protein consisting of VEGF receptor extracellular domains fused with the Fc portion of human IgG1 [which] contains portions of extracellular domains of 2 different VEGFRs.

Ziv-aflibercept inhibits both VEGFR1 and VEGFR2, and mTORC1/mTORC2 pathway inhibitors, such as sapanisertib, also inhibit the activity of several downstream pathways that have antiangiogenic activity and confer decreased antiangiogenic activity. mTOR inhibitors can be combined with VEGF inhibitors safely and have shown combination activity. That provides the clinical and preclinical rationale of combining an agent such as ziv-aflibercept with an mTORC1/2 potent agent such as sapanisertib.

This was a phase 1 study, and the primary objective was to [determine] the maximum tolerated dose [MTD] and the recommended phase 2 dose [RP2D] in 55 patients enrolled in the study. Sapanisertib [was administered at a dose of] 4 mg orally 3 days on and 4 days off in combination with 3 mg/kg of ziv-aflibercept given intravenously every 2 weeks on a 28-day cycle and a MTD was defined. Many of the grade 2 adverse effects [AEs] included hypertension, fatigue, anorexia, [and] hypertriglyceridemia. In terms of efficacy, from the data set of 50 patients with evaluable disease, 74% achieved SD as best response, 4% achieved a confirmed PR, and the DCR was 78%.

What was the rationale for combining sapanisertib with metformin in patients with advanced cancers?

mTOR inhibitors have been approved by the FDA for treatment of patients with advanced renal cancer, advanced breast cancer, and several other cancers. These mTOR inhibitors, such as everolimus [Afinitor], mainly target the mTORC1 pathway. The next generation mTOR inhibitors, such as sapanisertib, are potent ATP-competitive dual pathway inhibitors of both mTORC1 and mTORC2.

In phase 1 and early phase studies, sapanisertib demonstrated anti-tumor activity in renal cell carcinoma and endometrial cancer. Metformin is a common antidiabetic medication that has been repurposed as an antineoplastic medication to enhance the effect of chemotherapy in multiple cancers. The mechanisms attributed to the anti-hyperglycemic effects of metformin include the activation of AMPK, decreased production of cyclic AMP, suppression of mitochondrial complex I of the electron transport chain, glycerophosphate dehydrogenase targeting, and, interestingly, metformin can also add to the gut microbiomes.

Metformin inhibits the mTOR pathway through upstream activation of AMPK, which results in the phosphorylation and activation of the tumor suppressor gene TSC2; this decreases the downstream AKT activation and [exerts an] inhibitory effect on mTOR. Synergistically this could interact with the mTOR pathway. Preclinically, metformin induced activation of AMPK, which has [been] shown to disrupt the cross-talk between IGF1R and G protein–coupled receptors in many cancers.

In addition, several population studies have shown a decrease in the mortality rate of patients [being treated with] metformin, especially for the management of diabetes. This provides a rationale that metformin can be combined with sapanisertib. Both [agents] target the mTOR pathway [and] could complement each other. [Metformin could] enhance the anti-tumor activity of an mTORC1 and mTORC2 [targeted] drug like sapanisertib.

Interestingly, of the 30 evaluable patients for response who received sapanisertib and metformin, 4 patients achieved a PR and 15 patients achieved SD. The DCR was 63%. Out of responders that achieved a PR, 3 out of the 4 patients had documented PTEN mutations and 3 of the 5 patients enrolled with PTEN mutations had a PR. Two of the 4 patients who achieved a PR had comutations [of] PTEN and TSC, [and] a patient with breast cancer had comutations of PTEN and STK11. One of the 4 patients who achieved a PR had AKT and mTOR mutations. [Activity was seen with the combination in] challenging tumor types [to treat] such as leiomyosarcoma, breast cancer, and endometrial cancer.

How could sapanisertib fill an unmet need for patients with advanced solid tumors?

Sapanisertib has shown anti-tumor activity in patients with advanced malignancies, especially in combination with metformin—it showed activity in patients harboring PTEN mutations, [as well as]AKT and mTOR pathway alterations. The combination of sapanisertib and [a] VEGF1/2 inhibitor also showed anti-tumor activity in heavily pretreated patients. Sapanisertib is a combination player; as PI3K/AKT/mTOR pathways [are] concurrently activated [in] multiple tumors, [and] it may be worthwhile to explore combination therapy with agents with non-overlapping toxicities here.

Sapanisertib plus metformin [had a] generally well tolerated safety profile. The combination of sapanisertib and the VEGF1/2 inhibitor ziv-aflibercept was generally well tolerated [too], and there were no unexpected safety events other than what we would see with sapanisertib or ziv-aflibercept [monotherapy].

What would you like your colleagues to take away from this research?

We need to analyze the responders deeply. Three out of the 4 patients who achieved a PR [had a] double mutation; patients had documented alterations in PTEN and STK11, PTEN and TSC2, and AKT and mTOR, suggesting perhaps hyperactivation of the pathway is responsible for the responses to the combination. Interestingly, no objective responses were seen in patients harboring only PI3K mutations.

There are several limitations to these studies, including the small number of patients treated and the inclusion of many patients with comutations in addition to mTOR, AKT, and PI3K, which may affect underlying oncogenic driver pathway activity. Regardless, we’ve shown clinical activity in heavily pretreated patients [and] this regimen could prove an effective treatment option in specific biomarker driven subsets [of patients such as those with PTEN mutations].

What are the next steps for sapanisertib and TORC1/2 inhibitors in general?

The PI3K/AKT/mTOR pathway is concurrently activated in multiple tumors so it may be worthwhile for us as a field to explore combination therapies of mTORC2 pathway inhibitors with agents with non-overlapping toxicities. Many translational studies [have shown] that double mutations hyperactivate PI3K signaling with increased tumor growth in preclinical models. Also, early clinical data have shown that breast cancers harboring double mutations were more sensitive and responded better to PI3K inhibitors than those with single mutations.

[Therefore], it is possible that this double mutation in the same pathway is functioning similarly in other tumors beyond breast cancer. The next steps for agents targeting the mTORC2 pathway, and specifically sapanisertib, [include] combination studies in patients with double mutations as our research showed responders had double mutations in the same pathway. Theoretically, this can hyperactivate the pathway conferring sensitivity to these targeted agents.

As a field, we’ve been working on mTOR inhibitors for the past 25 to 30 years. [For] the past 2 decades, we’ve worked on mTORC1 inhibitors, and the development pathway of mTORC1 and mTORC2 inhibitors, the dual novel inhibitors, has been challenging because head-to-head [analyses of] several of these [agents] have not proven, at least in clinical models, to be superior to the traditional mTOR inhibitors, which target only mTORC1. But looking at responders in [certain] combination studies, dual mTORC2 inhibitors are a combination play and we need to test them in specific biomarker driven subgroups rather than a one-size-fits-all approach.

References

1. Subbiah V, Coleman N, Piha-Paul SA, et al. Phase I study of mTORC1/2 inhibitor sapanisertib (CB-228/TAK-228) in combination with metformin in patients with mTOR/AKT/PI3K pathway alterations and advanced solid malignancies. Cancer Res Commun. 2024;4(2):378-387. doi:10.1158/2767-9764.CRC-22-0260
2. Coleman N, Stephen B, Fu S, et al. Phase I study of sapanisertib (CB-228/TAK-228/MLN0128) in combination with ziv-aflibercept in patients with advanced solid tumors. Cancer Med. 2024;13(3):e6877. doi:10.1002/cam4.6877