1 week Ago
Pamela T. Soliman, MD, MPH Each research step that reveals patterns of activity with targeted therapies in endometrial cancer—such as metformin and temsirolimus (Torisel)—brings the field closer to developing increasingly effective and better-tolerated regimens that improve upon historical treatment results and quality of life (QOL) outcomes, according to Pamela T. Soliman, MD, MPH.
Soliman and colleagues conducted a phase 1 trial (NCT01529593) investigating the combination of temsirolimus plus metformin in patients with advanced or recurrent endometrial cancer. Among 33 response-evaluable patients, 2 (6%) achieved an overall response; both were partial responses (PRs). 1 Additionally, 13 patients (39%) had stable disease (SD), which lasted at least 4 months in 11 patients, translating to a clinical benefit rate of 39%.
“The future [of endometrial cancer therapy hinges on the question]: How do we identify patients who would benefit from the strategy of targeted therapy, and what is the right combination to give them the maximum benefit with manageable toxicity?” Soliman said in an interview with OncLive ® . In the interview, Soliman discussed how the mechanisms of action of temsirolimus and metformin helped prompt the investigation of these agents in combination in patients with recurrent endometrial cancer, the findings from this phase 1 trial, and how these results may inform future research directions regarding the identification of patient subsets for targeted therapy and the exploration of combination regimens with other classes of agents. Soliman is a professor in the Department of Gynecologic Oncology and Reproductive Medicine in the Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston.
Soliman : Temsirolimus is an mTOR inhibitor, [and approximately] 50% of patients with endometrial cancer have an abnormality in the PTEN/AKT pathway. One of the ways we’ve tried to treat endometrial cancer is by targeting some of those steps. We first conducted studies with mTOR inhibition approximately 20 years ago, and we recognize that mTOR inhibitors alone don’t have a lot of activity for cancer shrinkage, but combining them with other drugs can enhance [their anticancer effects].
Several different [mTOR inhibitor-based] combinations have been evaluated, but the rationale for including metformin [in the doublet] is that metformin also works in patients with insulin resistance, and one of the downstream effects of metformin is that it potentiates the same pathway [as temsirolimus] and can co-inhibit mTOR. Additionally, patients with endometrial cancer often have insulin resistance, so addressing that and increasing the uptake of insulin in the peripheral circulation may inhibit endometrial cancer. We’ve performed preclinical studies examining tissue-level data that show that metformin affects endometrial cancer cells.
There are a lot of cell line data, [and] metformin has been investigated in endometrial cancer in other studies as well. A large phase 2/3 study [NCT02065687] added metformin to chemotherapy in patients with advanced disease, but unfortunately, that [combination] didn’t show much benefit. We’ve done studies here at MD Anderson evaluating a different mTOR inhibitor—the oral agent everolimus [Afinitor]—in combination with letrozole, which is an antihormone agent, and added metformin as a third drug.
The addition of metformin seems to play a role in this combination, [but] we have not perfectly figured out where we can elicit the biggest benefit or which patients would benefit the most [from this agent]. This was a true phase 1 study, and the [article published in Gynecologic Oncology in January 2025] reports on the dose-expansion cohort. Once we identified a tolerable dose [of temsirolimus plus metformin], we treated a larger number of patients to evaluate overall efficacy and response rates.
Unfortunately, [the combination] wasn’t as effective as we were hoping. In a total of 40 patients who were enrolled, 33 patients were evaluable for response, meaning that they were able to receive at least 1 cycle of treatment and undergo follow-up imaging to evaluate them as well. Unfortunately, there were only 2 patients who had a PR where the tumor shrank more than 30%.
[Furthermore], 13 patients—[39% of the population]—had SD over time, even though they didn’t experience tumor shrinkage. [Regarding the] population of patients with recurrent disease who have received several different prior therapies, what I often tell patients is even if we can get cancer control—even if [the tumor] doesn’t shrink, but the cancer can be stabilized over time and patients can tolerate therapy—that still benefits them in the long run. If you combine the few responses and the higher percentage of SD [observed in this phase 1 trial], some patients obtained benefit from this combination.
We’ve seen in different studies of metformin that you can add the drug to other [agents], and it doesn’t increase toxicity much; it’s a well-tolerated and safe drug. These studies were ongoing [at the time we started the phase 1 trial], but in a phase 2 trial [NCT01797523] that was published [in Clinical Cancer Research in 2020], we had already added metformin to the combination of everolimus and letrozole [in patients with advanced or recurrent endometrioid endometrial cancer]. [In that study], we found that the response rates with that triplet combination were higher [than those in our phase 1 trial of metformin plus temsirolimus, as 28%] of patients achieved a response.
2 At 6 months in that trial, 41% [95% CI, 27%-54%] of patients were progression free. There are patients who benefit from the combination [of metformin and mTOR inhibition]. As with a lot of the mTOR inhibitors, one of the adverse effects associated with temsirolimus is hyperglycemia, [which is important to note].
We’re still trying to figure that out, and one [element] is patient identification. Increasingly in endometrial cancer [management], we’re using patients’ molecular subtypes or molecular classifications to guide cancer therapy to consider which patients truly benefit from these medications. Since this trial, [the treatment paradigm has expanded to include] newer-generation mTOR inhibitors and AKT inhibitors, [and] a lot of agents are in ongoing trials.
We’re also examining other [potential drug combinations]. For example, in addition to antiestrogen therapy, is there a role for CDK4/6 inhibitors that potentiate the same pathway? There have been a lot of strides in endometrial cancer [management] over the past couple years. Targeted therapies were the first types of treatments that significantly improved response rates and tolerability over chemotherapy [in this disease].
There continue to be newer generations of drugs. A lot of the AKT and PI3K inhibitors are associated with a fair amount of toxicity. Many of the questions we ask during drug development include: Are we hitting the right target, and is the medication tolerable? Future research is moving targeted therapies in a forward direction, and we’re also incorporating other strategies.
Is there a subset of patients who would benefit from immunotherapy? Many novel and interesting antibody-drug conjugates are also targeting different pathways. The future is bright. [The field] has changed a lot in the past 5 years for endometrial cancer, which is great, and in the coming years, we’ll see further development of all these strategies.
Overall, the [treatment] strategy with a lot of patients with advanced or recurrent disease is: How can we improve their survival, help them live longer, and help them have a good QOL? Although we were hoping for better responses, one of the takeaways from this study is that patients didn’t experience much toxicity. Temsirolimus plus metformin was a tolerable [regimen], and some patients experienced benefit. With future studies, we’re trying to get more cancer control or higher response rates, but it’s important to also consider toxicity and tolerability because helping patients live longer [and] making sure they have a good QOL are equally important.
In this patient population, where we’re trying to give patients the best treatment option, offering patients a clinical trial, in general, allows us to get a better idea of response rates and tolerability for a lot of these newer drugs. At MD Anderson, it’s a priority for us to put patients on trials, and this should be considered in every practice setting. By offering patients clinical trial options, we will have the best ability to identify better treatment options for women with endometrial cancer [who experience disease] recurrence.
.
