The Role of mTOR/Aurora A Kinase Combination Therapy Requires Further Elucidation in Solid Tumors

Although combination therapy with the mTOR inhibitor sapanisertib and Aurora A kinase inhibitor alisertib (MLN8237) resulted in marginal clinical benefit among patients with advanced solid tumors, correlative analyses indicated that apoptotic response and tumor immune cell infiltrate may affect clinical outcomes. Data from an expansion cohort of the phase 1b study (NCT02719691) also showed that select patients had positive outlying responses, according to lead study author S. Lindsey Davis, MD.

“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 enough [of an efficacy] signal to take this to a large phase 2 clinical trial in a certain disease state,” Davis said. “The importance of these findings is also further evaluated in 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.”

Initial data among 18 patients treated with sapanisertib plus alisertib in the phase 1 dose-finding portion of the study demonstrated that 1 patient with hormone receptor–positive, HER2-negative breast cancer and 1 patient with castration-resistant prostate cancer experienced prolonged stable disease (SD). Therefore, the expansion cohort enrolled 20 patients with refractory solid tumors. In this 20-patient cohort, 1 patient with hormone receptor–positive HER2-negative breast cancer achieved a partial response (PR) and 1 patient with refractory pancreatic adenocarcinoma experienced prolonged SD for approximately 11 months.

Following these findings in the expansion cohort, an additional 11 patients were enrolled in a pancreatic cancer expansion cohort. Of the 6 evaluable patients with pancreatic cancer in the cohort, 67% experienced SD with 1 patient experiencing SD for more than 6 months.

In an interview with OncLive^®, 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, highlighted data from the expansion cohort including correlative findings, and possible next steps with sapanisertib.

OncLive: What was the rationale for combining sapanisertib with alisertib in patients with advanced solid tumors?

Davis: Dr Jennifer Diamond, MD, who is the principal investigator of this [trial], evaluated alisertib in preclinical models of triple-negative breast cancer [TNBC] in previously published work. Her group observed upregulation of genes in the PI3K/AKT/mTOR pathway in preclinical models. They treated TNBC models to resistance; the point at which the treatment stopped working and the tumor started growing is where this upregulation of the mTOR pathway was identified.

Based on this finding, the next step in the laboratory was to add an mTOR inhibitor to the Aurora A kinase inhibitor. [When we did that] increased anti-cancer activity with the combination in these TNBC models [was observed]. Other [data] have confirmed this finding of activation of the mTOR pathway as a resistance mechanism for Aurora A kinase inhibitors such as alisertib in TNBC and other solid tumors. That was the impetus to take this combination to the next step into the clinic for a clinical trial.

What early efficacy data were seen with this combination?

In the expansion cohort, we treated 20 additional patients with the combination of sapanisertib and alisertib at the recommended phase 2 dose. Unfortunately, the efficacy with the combination was modest in this group; in 16 of the patients who we had evaluable scans for the overall response rate was only 6%. There was a SD rate of 38% and the DCR was 44%, but this was still considered modest overall.

However, in that group of patients, there was 1 patient with refractory pancreatic adenocarcinoma who had prolonged SD for [approximately 11 months]. That led us to say, ‘wow, this is a standout patient, [because] this is a very refractory disease that is difficult to treat.’ Therefore, we enrolled an additional 11 patients with pancreatic adenocarcinoma refractory to standard treatments in [another] cohort. Unfortunately, we also saw quite modest responses to treatment [in that population], but we did gather those data as well given that outlier patient with an impressive response.

What data have been seen so far regarding safety with sapanisertib?

The most common adverse effects [AEs] we documented in the original dose escalation were neutropenia, fatigue, nausea, mucositis, and rash. Most of these were mild. There were AEs in the intermediate dose level that [we] identified [as] dose-limiting toxicities; these included grade 3 and 4 neutropenia and fatigue. There was [also] some intolerable nausea because patients were [being] maximally treated and had to skip a lot of doses in that group.

In this expansion cohort, we collected additional safety data and found similar patterns [with] fatigue, diarrhea, nausea, and mucositis [reported]. In this group, abdominal pain was considered a treatment-emergent AE not necessarily attributed to the drugs, but we had a lot of patients with pancreatic cancer, so patients with pain. Most of these [AEs observed] were mild.

One toxicity that we were monitoring closely for that is specific to mTOR inhibitors is hyperglycemia. In our trial, this was mild, but it is a toxicity of interest because the mTOR pathway has an important role in glucose homeostasis. 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.

In the expansion cohort of patients, neutropenia was not [among] the most common AEs, but it was the AE that was of the highest grade; 13% of patients had grade 3 or 4 neutropenia at the recommended dose for this combination. It was tolerable from an oncology perspective. There are many agents and combinations that have this [AE occur with treatment], but it is important to know about the combination should it be taken further into clinical use.

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

We all hope so. There are many cancers [in which] the mTOR pathway is upregulated or important for oncogenesis and metastasis in general—by no means does this suggest we need to give up on that. Our work provides an example of developing a rational combination for mTOR inhibitor [therapy]; identifying places where upregulation of mTOR may be a mechanism of resistance is the overall theme that this work adds [to].

It does not necessarily have to be Aurora A kinase inhibitors, but other therapies could be approached in a similar way to come up with rational combinations. Evident from our work, there are probably subgroups of patients with various solid tumor types who are more likely to benefit. A big focus on preclinical work and correlative study work evaluating pre/post [treatment] tumor tissues trying to identify the underlying mechanisms by which these standout patients are benefiting is going to help us better tailor treatment to the patients it is most likely to help.

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

The key takeaway is that combining a second-generation mTOR inhibitor such as sapanisertib with an Aurora A kinase inhibitor is safe. Toxicities are expected for what we anticipate with these drugs as single agents, and overall, the AEs we observed were generally mild in severity. Although these results don’t give us a next step in terms of a clinical use, it does still give us hope that maybe there are other [patients] like these few patients with prolonged stabilization of disease. Encouraging more work in this space to try to identify [those patients is important].

Our efforts with correlative studies suggest that in patients [from the expansion cohort] there is variability in patterns of apoptosis at the cellular level. We did biopsy samples in the initial 20 patients in the expansion cohort before treatment. A run in of sapanisertib in half the patients and alisertib in another half of the patients by itself first [was conducted]. We did a biopsy at baseline, after 1 week of single-agent treatment, and after 1 week of combination therapy and compared various correlative studies and those tumor tissue samples to understand whether the combination improved the pharmacodynamic profile of single-agent therapy.

What stood out [was 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. 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.

What are next steps for this agent and TORC1/2 inhibitors?

It’s exciting to see where these combinations may lead. 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]. The other excitement we had was seeing this immune infiltration, which we weren’t anticipating with this combination; [this] lends us to ask whether there is a role for combination [therapy] with immune targeting treatments. We’ll be excited to see where other combinations may lead and help with efficacy of the mTOR inhibitor pathway agents.

Reference

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