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ImmunotherapyEndometrial Cancer

Beyond Chemotherapy: Immunotherapy Offers a New Treatment Option for Women with Endometrial Cancer

Dr. Binder, of the University of California, San Diego, describes immunotherapy as the most recent advance in the treatment of endometrial cancer.
November 2022 Part 2 of 2 – Endometrial Cancer Special Issue Series
Pratibha S. Binder, MD
Gynecologic Oncologist
Assistant Professor of Obstetrics, Gynecology, and Reproductive Sciences
University of California, San Diego, CA

Did you know that your own immune system has the ability to fight against cancer cells? Scientists have been studying the role of the immune system in recognizing and fighting cancer cells for over a century, but it has been only in the past few decades that multiple drugs that activate or turn on and regulate the immune system have been approved for the treatment of some cancers. Some of these immune activators and regulators, what is collectively called “immunotherapy,” have recently been approved for the treatment of endometrial cancer, a cancer arising in the inside lining of the uterus.

The First Immunotherapy

The first immunotherapy drug tested in endometrial cancer clinical trials actually was approved very rapidly because it proved its benefit to cancer patients who had endometrial cancers with a certain immune environment, or “signature.” This is known as an accelerated approval, and the drug was pembrolizumab, which is currently used for the treatment of solid organ cancers that have spread elsewhere in the body, including endometrial cancer, that expresses a specific type of immune signature. After this accelerated approval in May 2017, pembrolizumab received full approval for endometrial cancers with that same immune signature in March 2022. You may be asking “What is this pembrolizumab, how does it work, and what do you mean by immune signature?” Please allow me to explain.

How Does the Immune System Fight Cancer?

The immune system works by identifying foreign or “non-self” cells and then secreting chemicals that activate other parts of the immune system to fight against the foreign cells. This is how our body recognizes infections and then fights off bacteria and viruses that do not belong. Similarly, cancer cells are foreign because they have mutated enough to start looking different from our normal cells. However, our immune system does not fight cancer the same way it fights infections. This is because cancer cells have learned how to evade our immune system by either hiding from it or by putting on the brakes to deactivate or turn off the immune system. This is where pembrolizumab comes in. Pembrolizumab takes these brakes off and allows the immune system to recognize cancer cells as foreign again and also allows activation of our “killer immune system” that then does the job of killing cancer cells.

What Is an Immune Signature?

Pembrolizumab itself works quite well in cancer cells that have a lot of mutations and have a lot of unrepaired DNA damage because those cancer cells look more foreign. That is the immune signature I mentioned above. Scientifically speaking, pembrolizumab is usually effective in cancers with a mismatch repair-deficient, microsatellite instability-high, or tumor mutational burden-high status. Special pathology tests are done to determine if the cancer cells display these features. Pembrolizumab was approved for the treatment of recurrent endometrial cancers with these immune signatures that cannot be cured with alternative anticancer treatment options, such as surgery, radiation, or chemotherapy.

While pembrolizumab led to a response in 46% of cancers with the above immune signature, it did not work so well in the patients with mismatch repair-proficient, microsatellite instability-low, and tumor mutational burden-low endometrial cancer status.1 For these patients, another clinical trial was performed combining pembrolizumab with lenvatinib (a targeted treatment that inhibits cellular pathways and growth), and one study showed a response rate of 40% with this combination.2 Another confirmatory study was done to show that patients receiving pembrolizumab with lenvatinib survived without their cancer progressing for almost twice as long as patients receiving chemotherapy (6.6 months vs 3.8 months).3 The combination of pembrolizumab and lenvatinib was granted accelerated FDA approval in September 2019 and received full approval in July 2021.

Side Effects

The most common side effects of pembrolizumab can include fatigue, rash, musculoskeletal pain, diarrhea, fevers, cough, decreased appetite, itching, shortness of breath, constipation, pain, abdominal pain, and nausea. In some cases, pembrolizumab can overactivate the immune system to a point where it can affect normal glands and normal human organs, including the thyroid gland, pancreas, adrenal glands, lungs, colon, and others. Physicians using pembrolizumab are very well versed in the adverse effects and are constantly evaluating patients for early signs of any side effect. When pembrolizumab starts affecting normal organs, it is usually treated with corticosteroids, which suppresses the immune system temporarily.

The Future of Immunotherapy

Other immunotherapy medications, including dostarlimab, that work similarly to pembrolizumab have also been approved in the treatment of endometrial cancer. Immunotherapy is now also being studied in first-line treatment of endometrial cancer to see if incorporating these medications earlier can lead to higher cure rates in both early- and advanced-stage patients.

Conclusion

If you are dealing with a recurrence of your endometrial cancer and have not yet heard about immunotherapy, ask your treating oncologist if you might be a candidate now or in the near future. Some women get second opinions at large academic cancer centers so that doctors who specialize only in the treatment of endometrial cancer can weigh in on what your options may be now or later. Immunotherapy is now also being studied in endometrial cancer clinical trials at initial detection and diagnosis if the risk of recurrence is high enough to warrant anticancer therapy. Ask your treating oncologist if you are a candidate for a clinical trial near you.

References

  1. O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab in patients with microsatellite instability–high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol. 2022;40:752-761.
  2. 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;20:711-718.
  3. Makker V, Colombo N, Herráez AC, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022; 386:437-448.

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