by Dr. C.H. Weaver M.D. updated 4/2023
Uterine cancers can be hard to detect and are usually diagnosed when they are advanced. Although these cancers can be held at bay with surgery or chemotherapy, they often return and become difficult to control. Researchers have been exploring whether harnessing the power of the immune system could be beneficial.
There are logical reasons to think that endometrial (uterine) cancers may respond to immunotherapy. Some of these cancers carry genetic mutations that are known to respond to these drugs. Others bear clinical markers showing that the immune system is already primed to respond.
Endometrial cancer begins in the inner lining of the uterus, which is known as the endometrium. In the U.S., it is estimated there will be almost 66,000 women diagnosed with uterine body cancer and nearly 13,000 deaths from the disease in 2020. The five-year survival rate for advanced or metastatic endometrial cancer (stage IV) is estimated to be approximately 17% and hasn’t been significantly improved for several years.
Endometrial Cancer: Boosting Checkpoint Inhibitors
One type of immunotherapy showing promise is a class of drugs called immune checkpoint inhibitors.
Immune checkpoint inhibitor drugs are currently the most widely used and publicized precision immunotherapy treatment. A patient’s cancer cells can express molecules that activate PD-1 or CTLA-4 inhibitory “receptors” on their “T-cells” or other cells in the immune system. When these receptors are activated on the T-cells, they are prevented from attacking the cancer cells and evade the immune response. Checkpoint inhibitor drugs that block PD-1, PD-L1, or CTLA-4 work to “release the brakes” allowing the cancer cells to be detected and attacked by T-cells.
A major development was the FDA approval of Keytruda (pembrolizumab) – a checkpoint inhibitor for cancers that have a genetic abnormality called mismatch repair (MMR) deficiency. This genetic flaw prevents cells from fixing mistakes that occur when DNA copies itself. As a result, MMR-deficient cells (dMMR) can have hundreds or even thousands of mutations, compared with just a few dozen in a typical cancer cell. This pattern of widespread genetic change is called microsatellite instability.
The effectiveness of checkpoint blockade drugs against MMR-deficient tumors bodes especially well for the treatment of endometrial cancer, since about 30% of endometrial tumors are MMR-deficient. The approval of Keyturda for the MMR subtype of endometrial cancer was the proof of principle that this type of immunotherapy can be successful in a gynecologic cancer.
Results from phase III clinical trials reported at the Society of Gynecologic Oncology annual meetings confirmed that the addition of Keytruda immunotherapy to treatment regimens for endometrial carcinoma improve overall survival, and delays cancer progression.1,5
Keytruda + Chemotherapy
In the phase-3 NRG GY018/Keynote-068 clinical trial the addition of Keytruda immunotherapy to standard chemotherapy significantly delayed cancer progression compared with chemotherapy alone in patients with advanced or recurrent endometrial cancer. In the trial 816 patients with measurable stage III/IVa, IVb, or recurrent endometrial cancer were treated with Taxol (paclitaxel) and carboplatin chemotherapy with or without Keytruda and directly compared.
All patients appeared to benefit from the addition of Keytruda to standard chemotherapy, however the greatest benefit was in patients who were dMMR – their risk for cancer progression or death was reduced by 70%. One year from treatment 74% of dMMR Keytruda treated patients survived cancer free compared with 38% of patients treated with chemotherapy alone.5
Keytruda + Lenvima
Lenvima is a multikinase receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1-3. Lenvima™ also inhibits other RTKs that have been implicated in cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4 and the platelet derived growth factor receptor alpha (PDGFR), KIT, and RET.
The Keytruda-Lenvima combination was evaluated in 827 women with advanced uterine cancer and directly compared to “physicians’ choice+ of doxorubicin or Taxol chemotherapy.
The combination delayed cancer progression and prolonged survival in all patients, including those with proficient mismatch repair. Average survival duration improved from 11 to 18 months.6
The addition of Lenvima to Keytruda may have more side effects than the Keytruda chemotherapy combination. Overall, 89% of patients who received Keytruda-Lenvima had side effects and dose reductions were required in 1/3 of patients compared to only 8% of those treated with chemotherapy.
These trials confirmed the benefit of a previous smaller trial of patients with metastatic endometrial cancer that led to the United States Food and Drug Administration (FDA) granting accelerated approval to the combination of Keytruda and Lenvima for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) and are not candidates for curative surgery or radiation based on this and additional information.2,3
MSI-H and dMMR Disease
The U.S. Food and Drug Administration approved Keytruda as a single agent for the treatment of patients with advanced endometrial carcinoma that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression. The approval is based on the KEYNOTE-158 trial which reported an overall response rate of 46% and a complete response rate of 12%. Of the responding patients 68% had responses lasting 12 months or longer, and 44% had responses lasting 24 months or longer.
The KEYNOTE 775 clinical trial enrolled patients with MSI-H or dMMR tumors and positive results were observed in both mismatch repair proficient (pMMR) and MSI-H/dMMR patients.
The combination of Keytruda with standard chemotherapy or Lenvima provides meaningful benefit to women with advanced uterine cancer. The addition of Keytruda immunotherapy should be considered in all women with advanced or recurrent endometrial cancer.
References:
- Lancet Oncol. 2019 Mar 25. Epub ahead of print.
- FDA takes first action under new international collaboration with Australia and Canada designed to provide a framework for concurrent review of cancer therapies, approving treatment for patients with endometrial carcinoma.. Accessed September 17, 2019 FDA website. Posted September 17, 2019.
- Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20(5):711-718. doi: 10.1016/S1470-2045(19)30020-8
- Makker V, Colombo, N, Casado Herráez A., et. al. A multicenter, open-label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: Study 309/KEYNOTE-775. Annual Meeting of the Society of Gynecologic Oncology, 2021.
-
https://www.nejm.org/doi/full/10.1056/NEJMoa2302312?query=featured_home
-
Makker V, Lorusso D, Moore R, et al. Characterization of tumor response with lenvatinib plus pembrolizumab in study 309/KEYNOTE-775. Presented at: 2023 Annual Meeting on Women’s Cancer; March 25-28; Tampa, Florida.
