Dual Targeting of the mTOR Pathway May Enhance Antitumor Activity in Solid Malignancies

Vivek Subbiah, MD

Several recent studies examining novel mTOR inhibitors in combination with various agents, from inhibitors of VEGF, Aurora A kinase, and PD-1 to an antidiabetic agent, have shed light on how mTOR inhibitors may be combined safely with additional therapies for patients with solid tumors. Sapanisertib (CB-228), a dual inhibitor of mTORC1 and mTORC2, is an mTOR inhibitor of particular interest, and findings from phase 1 studies showed promising safety signals when combination therapy with the agent was evaluated in various solid tumors, including cervical and pancreatic cancer.^1-3

“mTOR exists in 2 physically and functionally distinct protein signaling complexes—one with Raptor, which is sensitive to the mTOR inhibitor rapamycin, and the other with Rictor, which is rapamycin insensitive,” Vivek Subbiah, MD, chief of early-phase drug development at Sarah Cannon Research Institute in Nashville, Tennessee, said in an interview with OncologyLive (Figure⁴). “The currently approved rapalogs such as rapamycin or everolimus [Afinitor] exert that inhibitory effect predominantly via the mTORC1 pathway, while the inhibitory effect of mTORC2 is very limited or weak. Consequently, there is continued signaling through significant pathway and feedback loops resulting in upregulation of other pathways like AKT, which has an undesirable effect of accelerating not only the cell proliferation but antagonizing the antiproliferative effects of the original mTOR inhibition.”

Figure. mTOR Pathway Signaling⁴

Previously, sapanisertib received fast track designation from the FDA in October 2022 for use as monotherapy in patients with unresectable or metastatic squamous non–small cell lung cancer harboring an NRF2 mutation who previously received platinum-based chemotherapy and immune checkpoint inhibition.⁵ Studies have also suggested that combination therapy may enhance the antitumor activity of sapanisertib.

“We needed next-generation mTOR inhibitors that not only target mTORC1 which is a Raptor pathway, but also target the Richter pathway. We have next-generation dual inhibitors of mTORC1 and mTORC2 and these have been developed, and preclinical models have supported the potency of the dual inhibitor strategy. Sapanisertib is a potent, selective ATP competitive dual inhibitor of mTORC1 and mTORC2 regulated by upstream tyrosine kinases such as IGF1R, and in early phase clinical trials, sapanisertib was shown to have preliminary anti-tumor activity,” Subbiah added.

Sapanisertib Plus the Antidiabetic Agent Metformin

“Metformin is a common antidiabetic medication that has been repurposed as an antineoplastic medication to enhance the effect of chemotherapy in multiple cancers,” Subbiah explained. “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.”

Subbiah noted that when the combination of mTOR inhibitors and metformin was used in preclinical models, “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 a phase 1 study (NCT03017833) that evaluated the combination of sapanisertib and metformin, 79% of response-evaluable patients with locally advanced or metastatic solid tumors (n = 19/24) achieved disease control. Partial responses (PRs) occurred in 17% of patients among those with leiomyosarcoma (n = 2), breast cancer (n = 1), and endometrial cancer (n = 1). The median progression-free survival (PFS) was 6.0 months (95% CI, 2.8-14.6) at a median follow-up of 19 months, and the median overall survival was 18 months (95% CI, 7.2-not evaluable).¹

“We need to analyze the responders deeply,” Subbiah noted. “Three out of the 4 patients who achieved a PR had a double mutation in the pathway; 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 [pathway] mutations.”

The maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination was sapanisertib 4 mg plus metformin 1000 mg daily (dose level 3). One patient experienced a dose-limiting toxicity (DLT) of grade 3 diarrhea when treated with sapanisertib 3 mg and metformin 1000 mg (dose level 2), which was managed with supportive therapies and without the need for dose reduction. Further, treatment with sapanisertib 4 mg given in combination with metformin 1500 mg (dose level 4) resulted in 2 DLTs of grade 3 fatigue in 1 patient and grade 3 rash in another patient; both patients were able to continue therapy following dose modification. In total, 13.3% of the 30 patients treated in the trial required a dose adjustment of either drug, and 10.0% needed a dose reduction of sapanisertib.

Among patients treated in the study, sarcoma (n = 6) was the most common cancer, followed by breast (n = 4), ovarian (n = 4), and head and neck (n = 3) cancers; 2 patients each also had colorectal, lung, renal cell, and endometrioid cancers, and 1 patient each had gastroesophageal junction, prostate, stomach, bladder, and cervical cancers.

“The next step should be to use these mTORC1/2 inhibitors in combination in specific biomarker-driven and targeted populations of patients, as we saw activity mainly in patients enriched with these pathway alterations,” Subbiah added.

Combining Sapanisertib With the Aurora A Kinase Inhibitor Alisertib

An expansion cohort of a phase 1b study (NCT02719691) evaluating sapanisertib with the Aurora A kinase inhibitor alisertib (MLN8237) in patients with refractory solid tumors found modest benefit with the combination, but correlative studies have the potential to shed light on select patients who did respond to the agents, according to lead study author S. Lindsey Davis, MD. Following initial efficacy demonstrated in the phase 1 dose-finding portion of the study (n = 18), where 1 patient with hormone receptor–positive, HER2-negative breast cancer and 1 patient with castrate-resistant prostate cancer experienced prolonged stable disease (SD), Davis noted the expansion cohort enrolled 20 more patients with refractory solid tumors to receive the combination at the RP2D.²

The RP2D was determined as alisertib 30 mg twice daily on days 1 through 7 of a 21-day cycle and sapanisertib 2 mg daily on a continuous schedule. Patients in the solid tumor expansion cohort received a 7-day lead-in of alisertib or sapanisertib prior to administration of the combination.

In the expansion cohort, 1 PR was seen in a patient treated in the alisertib lead-in group with hormone receptor–positive HER2-negative breast cancer, and 1 patient with refractory pancreatic adenocarcinoma experienced prolonged SD for approximately 11 months; therefore, 11 patients were enrolled to a pancreatic cancer expansion cohort.

In both lead-in groups, evaluable patients (n = 16) experienced a disease control rate (DCR) of 44% with a SD rate of 38% and an overall response rate (ORR) of 6%. Of the 6 evaluable patients in the pancreatic cancer expansion cohort, 67% experienced SD, and the remaining 33% experienced progressive disease; 1 patient experienced SD for more than 6 months.

“Our hope was that we could use this as a jumping-off point to move into a particular tumor type or do additional work in individual disease sites, [but] unfortunately, we didn’t see that signal enough to take this to a large phase 2 clinical trial in a certain disease state,” Davis, an oncologist at the University of Colorado Cancer Center and associate professor of medicine-medical oncology at the University of Colorado Anschutz Medical Campus in Aurora, explained.

“The importance of these findings is also further evaluated in those additional correlatives where we looked at tissue testing because there seem to be some standout patients. There are examples in our work of 3 patients in this group of [31] where we see outlying responses in a positive way. It speaks to the need for us to dig down into why those patients are the standouts and how we can tailor further treatments using sapanisertib and other mTOR inhibitors, either in this combination or others, to drive better benefit.”

Davis also noted correlative analyses were performed in a subset of patients enrolled in the solid tumor expansion cohort. These analyses suggested that apoptotic response and tumor immune cell infiltrate may affect clinical outcomes.

“[For] those who had a trend of longer time on study or more stabilization of disease, there was variability in the apoptosis seen in the patients getting combination therapies, and there were also variabilities in immune infiltration of tumors,” Davis said. “We believe there are probably unique gene expression and transcriptional profiles that contribute to this variability. [These are] very small numbers [of patients included in the analysis]; this is not enough to draw any conclusions, but there are hints that there could be different pathways that are helping those patients who had a better response to this treatment or a more prolonged stabilization of disease.”

Davis added that “the other excitement we had was seeing this immune infiltration, which we weren’t anticipating with this combination; [this] lends to ask, is there a role for combination [therapy] with immune-targeting treatments of any sort? We’ll be excited to see where other combinations may lead and help with efficacy of the mTOR inhibitor pathway agents.”

mTOR Pathway Inhibition Plus VEGF Inhibition Displays High DCR

Combining ziv-aflibercept, a recombinant fusion protein comprising VEGF receptor extracellular domains fused to the Fc portion of humanized IgG1, with sapanisertib yielded antitumor activity in patients with advanced solid tumors enrolled in a phase 1 study (NCT02159989). Among response-evaluable patients (n = 50) who were heavily pretreated receiving a median of 4 prior lines of therapy (range, 2-11) in the overall study population (n = 55), the DCR was 78%. Two patients achieved a PR, and of the 74% of patients who experienced SD, 4 patients had an unconfirmed PR; disease progression occurred in 22% of patients, including clinical progression of disease in 2 patients.

“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 they have shown combination activity as well.”

Sapanisertib administered orally at 4 mg for 3 days on and 4 days off plus 3 mg/kg ziv-aflibercept given intravenously every 2 weeks in a 28-day cycle was determined to be the MTD and RP2D. Additionally, no DLTs were observed in the expansion cohort of patients treated with this dose. Three patients experienced DLTs— grade 3 transient ischemic attack, gastritis, and dyspnea—when treated with higher doses in the dose escalation portion of the study.

Hyperglycemia: An Adverse Effect of Interest

The most common grade 2 or higher treatmentrelated adverse effects (TRAEs) among patients who received treatment with sapanisertib and ziv-aflibercept (n = 55) were hypertension (25%), fatigue (24%), anorexia (13%), hypertriglyceridemia (13%), diarrhea (11%), nausea (11%), mucositis (11%), and increased serum lipase level (11%). Grade 4 TRAEs occurred in 3 patients, including maculopapular rash, reversible posterior leukoencephalopathy syndrome, and increased lipase levels.³

Common grade 3 to 5 TRAEs occurring in patients treated with the combination of sapanisertib and metformin (n = 30) were hyperglycemia (13%), fatigue (7%), rash (7%), and diarrhea (7%), and hypertriglyceridemia, increased creatinine level, and acidosis occurred in 1 patient each. One patient also experienced a grade 5 TRAE of acidosis which was related to a hyperglycemia event.¹

“One toxicity that we were monitoring closely for that is specific to mTOR inhibitors is hyperglycemia,” Davis noted on combining sapanisertib with alisertib. “In our trial, this was mild, but it is a toxicity of interest because the mTOR pathway has an important role in glucose homeostasis and then when we interfere with that pathway with drugs such as sapanisertib we can affect the glycemic control. We saw that, we were looking for it, and we had patients closely monitoring their sugar levels. But we also found it to be very mild and something we didn’t need to adjust doses for,” she added.

Treatment-emergent AEs (TEAEs) occurring at any grade in all patients (n = 31) in the sapanisertib plus alisertib study most commonly included fatigue (58%), diarrhea (42%), nausea (42%), and abdominal pain (32%). Moreover, the most frequent any-grade TRAEs were fatigue (42%), mucositis (29%), hyperglycemia (26%), and nausea (23%). Grade 3/4 TEAEs included neutropenia (13%), abdominal pain (10%), mucositis (10%), and diarrhea (6%), with fatigue, hyperglycemia, hypokalemia, cognitive disturbance, and dyspnea occurring in 1 patient each.²

“Combining a second-generation mTOR inhibitor such as sapanisertib with an Aurora A kinase inhibitor is safe,” Davis said. “Toxicities are expected for what we anticipate with these drugs as single agents, and overall, the AEs we observed were generally mild in severity.”

Future Directions With mTOR Inhibitors: Phase 1/2 Trial Shows Promising Efficacy

Data from the phase 1/2 TORCH-2 trial (NCT04337463) presented at the 2024 American Society of Clinical Oncology Annual Meeting revealed that the novel second-generation TORC1/2 inhibitor onatasertib (ATG-008) was well tolerated and displayed promising efficacy when combined with the anti–PD-1 monoclonal antibody toripalimab-tpzi (Loqtorzi) in patients with cervical cancer (Table⁶). Among efficacy-evaluable patients (n = 30) the ORR was 53.3% (95% CI, 34.3%-71.7%) comprised of a complete response rate of 13.3% and PR rate of 40.0%. Additionally, 33.3% of patients experienced SD, and 13.3% experienced disease progression. The DCR was 86.7% (95% CI, 69.3%-96.2%), and the median PFS was 8.41 months (95% CI, 3.25-NE).⁶

Table. Efficacy With the Novel Second Generation TORC1/2 inhibitor Onatasertib in TORCH-2⁶

Additionally, 1 patient treated in TORCH-2 died due to a TEAE of myocarditis. Further, 45.2% of patients experienced a TEAE leading to dose modification, and 32.3% experienced serious TEAEs. Grade 3/4 TRAEs included rash (12.9%) and mucositis and hyperglycemia occurring in 1 patient each.

“It’s exciting to see where these combinations may lead,” Davis said. “Based on our experience, the interest of combined targeted therapies is exciting, and as these new therapies are evolving, how we might create these additional rational combinations [is a next step].”

Subbiah added, “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 mTORC1/2 inhibitors are more of a combination play than monotherapy and we need to test them in specific biomarker-driven subgroups as genomically targeted therapy trials rather than an all-comer, 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. Davis SL, Messersmith WA, Purcell WT, et al. A phase Ib expansion cohort evaluating aurora A kinase inhibitor alisertib and dual TORC1/2 inhibitor sapanisertib in patients with advanced solid tumors. Cancers (Basel). 2024;16(8):1456. doi:10.3390/cancers16081456
3. Coleman N, Stephen B, Fu S, et al. Phase I study of sapanisertib (CB-228/TAK-228/MLN0128) in combination with zivaflibercept in patients with advanced solid tumors. Cancer Med. 2024;13(3):e6877. doi:10.1002/cam4.6877
4. Conciatori F, Bazzichetto C, Falcone I, et al. Role of mTOR signaling in tumor microenvironment: an overview. Int J Mol Sci. 2018;19(8):2453. doi:10.3390/ijms19082453
5. Calithera receives FDA fast track designation for sapanisertib for the treatment of NRF2-mutated squamous lung cancer. News release. Calithera Biosciences Inc. October 3, 2022. Accessed June 20, 2024. https://www.globenewswire.com/news-release/2022/10/03/2526655/0/en/Calithera-Receives-FDA-Fast-Track-Designation-for-Sapanisertib-for-the-Treatment-of-NRF2-mutated-Squamous-Lung-Cancer.html
6. Yuan L, Shu P, Li X, et al. A phase 1/2 study of the TORC1/2 inhibitor onatasertib combined with toripalimab in patients with advanced solid tumors: cervical cancer cohort. J Clin Oncol. 2024;42(suppl 16):5509. doi:10.1200/JCO.2024.42.16_suppl.5509