Successful application of immunotherapy in endometrial cancer means identifying the patients with inflamed tumors who will respond to treatment and those who will not, and finding ways to treat noninflamed tumors with immunotherapy agents.
Kathleen N. Moore, MD
Successful application of immunotherapy in endometrial cancer means identifying the patients with inflamed tumors who will respond to treatment and those who will not, and finding ways to treat noninflamed tumors with immunotherapy agents, Kathleen Moore, MD, said at the 2019 SGO Annual Winter Meeting.1
Inflamed tumors, she said, are those such as POLε-mutated or microsatellite instability-(MSI) high tumors, that the immune system can recognize and kill. However, the process is more complicated than that.
“If that worked, we wouldn't have cancer at all. It would be something that was always taken care of by our innate surveillance systems,” said Moore, associate director for cancer research, director of the Oklahoma TSET Phase I Program Stephenson Cancer Center, and Jim and Christy Everest Endowed Chair in Cancer Research at the University of Oklahoma, and director of Gynecologic Oncology Fellowship at the University of Oklahoma Health Sciences Center.
“There are so many different elements that to contribute to what we call the individual's Cancer Immune Set Point,” she added. “This is where the personalization of medicine comes in and explains why some people do and don't respond to immunotherapy.”
Moore said there are preclinical data suggesting that these "hot" tumors are susceptible to immunotherapy. These tumors express increased infiltration with CD8 T cells in both the tumor and the surrounding stroma. Further, these tumors display a high preponderance of genes involved with T cell-mediated toxicity being expressed and transcribed such as TIM3, PD-L1, and LAG3. Moore added that these patients carry a high tumor burden and express a high number of neoantigens, which should mean they are primed to respond to immunotherapy.
"Additionally, tumors with POLε and MSI also make these things called tertiary lymphoid structures,” Moore said. “They're so inflamed and there's so many immune cells infiltrating the tumors, they actually try to create new lymph nodes in the tumor.”
The FDA's 2017 approval of pembrolizumab (Keytruda) as a tumor-agnostic treatment for MSI-high or mismatch repair deficient (dMMR) tumors further suggests that these tumors may respond to immunotherapy, she added.
Some receptors, such as TIM3 and LAG3, inhibit the T cell and others, such as CD28 and OX40 enhance T-cell activation. Investigators are exploring the possibility of targeting 1 such receptor in a phase I study (NCT03538028) of INCAGN02385, an antagonist antibody targeting LAG3 for the treatment of several MSI-high advanced malignancies that have progressed following treatment, including endometrial cancer.
“LAG3 alone may not be the right thing. We may have to use it in combination or maybe we have use it from the beginning. We don't know yet,” Moore said. “We're in our infancy of our understanding of how to use these drugs, but they are already in clinical trials in endometrial cancer.”
For immune-excluded or “cold” tumors, those where the immune system is activated but cannot get into the tumor, Moore said it may be possible to treat those with VEGF-inhibitors and by boosting T cell priming with chemotherapy. “VEGF is a highly immunosuppressive molecule. It's not just an angiogenic molecule,” she said. “It directly inhibits T-cell function and it inhibits T-cell trafficking to the tumor, which is why it's of interest in these immune-excluded tumors.
“There's a great deal of data in other tumors, renal cell being the key, showing that if you combine immune therapy with antiangiogenic agents like bevacizumab [Avastin], you improve the infiltration of previously excluded T cells into the tumor.”
Vikky Makker, MD, and colleagues evaluated the combination of the multikinase VEGF-inhibitor lenvatinib (Lenvima) plus pembrolizumab to treat patients with advanced endometrial cancer (NCT02501096). Patients with histologically confirmed disease irrespective of MSI or MMR status were assigned to 20 mg of daily lenvatinib plus 200 mg of pembrolizumab every 3 weeks.
In results presented at the 2018 ASCO Annual Meeting, Maaker et al found that the combination induced an overall objective response rate (ORR) of 39.6% (95% CI, 26.5-54.0) by independent investigator review with a duration of response not reached (range, 7.4 months-NR). The ORR was 50.0% (95% CI, 6.8-93.2) among the MSI-high subset (n = 4). The median progression-free survival (PFS) was 7.4 months (95% CI, 5.0-NR).2
Moore said the ORR for patients with recurrent disease is typically about 15% with a PFS of 3 months. “This is really an outlier when you think about data that has been presented in endometrial cancer,” she added.
Moore said that future research efforts should focus on understanding why patients in the inflamed subgroup fail to respond to immunotherapy, understanding why patients develop resistances and how to overcome those resistances. Additionally, more should be done to identify all patients in the inflamed subgroup, not just the MSI-high, so that these patients can receive immune checkpoint inhibitors.
“There's room for improvement there,” Moore concluded. “We've already shown it with lenvatinib and pembrolizumab, so I think there's reason to be very optimistic.”