CME

Article

Oncology Live®

Vol. 26 No. 5
Volume26
Issue 5

Combinations Targeting PI3K/ AKT/mTOR and MAPK/ERK Pathways Are Under Study in Endometrial Cancer

Author(s):

Combinations targeting PI3K/AKT/mTOR and MAPK/ERK pathways are under investigation to improve outcomes in patients with endometrial cancer.

Pamela T. Soliman, MD, MPH

Pamela T. Soliman, MD, MPH

The mTOR inhibitors everolimus (Afinitor) and temsirolimus (Torisel) were both evaluated as part of combination regimens for patients with recurrent endometrial cancer with the goal of targeting the PI3K/ AKT/mTOR and RAS/RAF/MEK/ERK pathways, which are integral in endometrial tumorigenesis.1 However, although many doublet or triplet therapies have been examined in this setting, including regimens encompassing the aforementioned drugs, they have shown limited efficacy.1,2

“At least 50% of patients with endometrial cancer have some abnormality in the PTEN/AKT pathway, [and] one of the ways we’ve tried to treat endometrial cancer is by targeting some of the steps along the [pathway],” Pamela T. Soliman, MD, MPH, said in an interview with OncologyLive. “The future [will revolve around a couple of questions]. How do we identify patients who would benefit from this strategy of targeted therapy? And what is the right combination to give them the maximum benefit but also make it with manageable toxicity?”

The PI3K/AKT and RAS/RAF/MEK/ERK pathways involve mTOR as an important downstream player, making mTOR inhibitors a rational component of regimens for this patient population. Additionally, metformin induces metabolic changes and activates AMPK, which in turn inhibits the mTOR pathway, providing the baseline for Soliman and coinvestigators to examine the antidiabetic agent in combination with temsirolimus.1 Soliman added that because patients with endometrial cancer often have insulin resistance, addressing that and increasing the uptake of insulin in the peripheral circulation may inhibit the cancer.

Building on Findings with mTOR Inhibition Plus an Antidiabetic Agent

In a phase 1 study (NCT01529593), treatment with the combination of temsirolimus and metformin yielded an objective response rate (ORR) of 6% of patients with endometrial cancer (n = 2 of 33). Stable disease (SD) occurred in 39% of patients (n = 13 of 33), and 11 patients experienced SD for at least 4 months; these data translated to a clinical benefit rate (CBR) of 39%.

“When we’re looking at a population with recurrent disease [after] a number of different prior therapies, what I often tell patients is even if we can get the cancer control—even if it doesn’t shrink, but the cancer is able to be stabilized over time and they’re able to tolerate therapy—that still benefits them in the long run,” Soliman said. “If you combine the few responses and the higher percentage of SD, there were some patients who got benefit from this combination.”

Additionally, no grade 4 or 5 treatment-related adverse effects (TRAEs) occurred in patients treated with temsirolimus plus metformin. Grade 3 TRAEs included anemia and thrombocytopenia, which each occurred twice, and mucositis, fatigue, hypokalemia, weight loss, hypophosphatemia, increased aspartate aminotransferase levels, and increased alanine aminotransferase levels, which all occurred once. The most common any-grade TRAEs among the 32 patients who experienced toxicities in the phase 1 study were hypertriglyceridemia (44%), mucositis (41%), diarrhea (41%), anorexia (38%), anemia (31%), and nausea (25%).

“Although we were hoping for better responses…patients didn’t experience much toxicity,” Soliman said. “It 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 look at toxicity and tolerability because helping people live longer [and] making sure that they have a good quality of life is equally as important.”

A previous study also examined metformin in combination with the mTOR inhibitor everolimus and the hormone therapy letrozole (Femara).2 Data showed the triplet elicited a CBR of 50% in patients with recurrent endometrial cancer (n = 54) and a partial response (PR) rate of 28%, with 22% of patients experiencing SD. Additionally, the median progression-free survival was 5.7 months (95% CI, 3.0-8.1), and the median overall survival was 19.6 months (95% CI, 14.2-26.3).

No patients experienced grade 5 AEs, and hypertriglyceridemia occurred at grade 4 in 1 patient. “With a lot of mTOR inhibitors, one of the AEs is hyperglycemia,” Soliman said. “We’ve seen in different studies of metformin that you can add the drug to other [agents] and it doesn’t increase toxicity very much; it’s a well-tolerated and safe drug. These studies were ongoing [at the time we started the phase 1 trial], but we had already added metformin in a different trial that was published a couple of years ago to the combination of everolimus and letrozole…. There seems to be some role in adding metformin, [but] I don’t think we’ve figured out perfectly where we can get the biggest benefit, or which patients would benefit the most.”

Additional Combinations Under the Microscope

As investigators believe metformin inhibits the mTOR pathway through upstream activation of 5’-AMPK, they combined it with the potent, selective adenosine triphosphate–competitive mTORC1/2 inhibitor sapanisertib in a phase 1 dose-escalation study (NCT03017833).3 Among 30 evaluable patients with solid tumors, 4 patients experienced a PR, which included 1 patient with endometrial cancer; 1 other patient with endometrial cancer was enrolled in the trial and experienced progressive disease.

Furthermore, the AKT/mTOR inhibitor ibrilatazar (ABTL0812) was also examined in patients with advanced/recurrent endometrial cancer and stage III and IV squamous non–small cell lung cancer not amenable to radiation in the phase 1/2 ENDOLUNG trial (NCT03366480).4 The combined patient population (n = 38) achieved an ORR of 65.8% (95% CI, 52.0%-78.9%), which included a complete response rate of 13.2% and a PR rate of 52.6%. Notably, the SD rate was 34.2%, and no patients experienced progressive disease, translating to a 100% disease control rate. Investigators of the trial noted that the data warranted further confirmation in prospective, randomized trials.

Further Homing In on Rational Combinations

When asked where research should go next with mTOR inhibitors, Soliman noted, “We’re still trying to figure it out, and one [element] is patient identification. More and more with endometrial cancer, we’re using patients’ molecular subtypes or molecular classifications to guide cancer therapy. Which patients truly benefit from these medications? Since [conducting] this [phase 1] trial, newer-generation mTOR inhibitors, AKT inhibitors, [and] a lot of agents [have emerged] in ongoing trials. We’re also looking at [potential] combinations with other drugs.

In addition to antiestrogen therapy, is there a role for [cyclin-dependent kinase] 4/6 inhibitors that also potentiate the same pathway?” Regarding molecular classification, a subgroup of patients with PI3K/ PTEN and RAS alterations who received temsirolimus plus metformin in the phase 1 study experienced SD.1 Investigators highlighted this as significant because approximately 22% of those with endometrial cancer have PIKC3A hyperactivity, approximately 42% to 54% of patients have PTEN mutations or repression, and 10% to 30% of patients have KRAS mutations. “In this patient population where we’re trying to give patients [with endometrial cancer] the best option, offering patients a clinical trial allows us to get a better idea of response rates and tolerability for a lot of these newer drugs,” Soliman said. “Here, it’s a priority for us to put patients on trials. It’s important wherever you’re practicing to consider clinical trials for these patients because there is an unmet need for women with endometrial cancer [who experience] recurrence.”

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