Endometrial Carcinoma Treatment Advances - Episode 3

Combination of I/O and TKI Therapy in Endometrial Cancer

Insight on the combination of lenvatinib and pembrolizumab in endometrial cancer, investigated between the KEYNOTE-146 and KEYNOTE-775 trials.


Brian M. Slomovitz, MD, MS, FACOG: Some of the biomarker-driven therapies, or even immunotherapies, for endometrial cancer are tyrosine kinase inhibitors, immunotherapy options, or checkpoint inhibitors. Tyrosine kinase inhibitors go after specific proteins that are overexpressed or have driven the pathogenesis within a cell. I refer to it almost as a weed killer, or a poison to the entire tumor, while tyrosine kinase inhibitors or other biomarker-driven therapies are like putting a stick in the spoke of the wheel. They’re not as damaging to the cells, but they go after a specific pathway.

In tumors that overexpress dysregulated proteins often found on the surface of the cell, tyrosine kinase inhibitors help limit their growth and proliferation. Immunotherapies work by stimulating the body’s immune system to recognize, kill, or stop proliferation of cancer cells. For example, a subset of endometrial cancers have microsatellite instability [MSI], or something called deficient mismatch repair [MMR] proteins. In those patients, those are recognized by the body as nonself, or something that shouldn’t be there. Adding a checkpoint inhibitor stimulates the body’s immune system to get rid of those cells.

When we talk about immunotherapy in endometrial cancer, the initial studies looked at treating women who had microsatellite instability with single-agent pembrolizumab, which was very effective. Also, the original studies looked at women who were biomarker negative, who did not have deficient mismatch repair, or MSI. Single-agent pembrolizumab did not work as well. KEYNOTE-146 was a combination study of pembrolizumab and lenvatinib in those women with biomarker negative, meaning microsatellite stable, or proficient MMR. In that study, there was good activity of this combination, even in those tumors that weren’t originally amenable to immunotherapy. By adding lenvatinib to the pembrolizumab, we got an acceptable response rate, which led to an accelerated FDA approval to use immunotherapy in combination with tyrosine kinase inhibitors [in biomarker-negative endometrial cancers].

After the initial accelerated approval, the confirmatory study for the combination of pembrolizumab and lenvatinib was KEYNOTE-775. In this second-line trial, the investigators, led by Vicky Makker at [Memorial] Sloan Kettering [Cancer Center], evaluated the pembrolizumab-lenvatinib combination vs chemotherapy. The 2 options were the 2 best options in second-line setting: doxorubicin or weekly paclitaxel. They found significant improvement in both progression-free survival and overall survival in women treated with pembrolizumab-lenvatinib and not chemotherapy.

This study included both dMMR [deficient MMR] and pMMR [proficient MMR], or both biomarker-positive and negative patients. Subset analyses of these data had been done. One subset analysis looked primarily at the dMMR patients, which also showed a benefit of the combination of pembrolizumab-lenvatinib when compared with the chemotherapy. One obvious question is do those patients need lenvatinib, or would pembrolizumab alone be enough? Another subgroup analysis looked at different histological subtypes, and it was interesting to find that pembrolizumab-lenvatinib worked across histological subtypes. Initially, we thought that endometrial cancer should be split and not clumped and treated by their histological subtype. However, in this subanalysis we found that all comers, not just in a particular histology, responded.

Transcript edited for clarity.