Endometrial cancer is rapidly increasing in Korea. Just 20 years ago, it had one of the lowest incidence rates among gynecologic cancers. However, it has now overtaken cervical cancer as the most common gynecologic cancer. Notably, the incidence is rising among young women, which calls for an aggressive response.

The treatment paradigm for advanced or recurrent endometrial cancer is also changing rapidly. While cytotoxic anticancer drugs have been the standard of care, immuno-oncology has recently emerged as a game changer in this field, improving survival chances.

“Immuno-oncology drugs have shown strong effects, especially for patients with recurrent or advanced mismatch repair deficient (dMMR)/high microsatellite instability-high (MSI-H), and in some cases, the treatment effect has improved to the point where cure can be expected,” said Professor Lee Yoo-young of the Gynecologic Cancer Center at Samsung Medical Center, during a recent interview with Korea Biomedical Review.

Recently, Jemferli (dostalimumab), the only anti-PD-1 immuno-oncology drug approved for the (second-line) treatment of endometrial cancer in Korea, received expanded indication from the Ministry of Food and Drug Safety (MFDS) to include the first-line treatment of patients with advanced or recurrent endometrial cancer without dMMR/MSI-H, making it a standard treatment option for all patients.

However, the fact that immuno-oncology drugs are still not reimbursed for first-line treatment remains an economic barrier for many patients. In the interview, Professor Yoo discussed the role of immuno-oncology in the rapidly changing treatment paradigm for endometrial cancer and offered recommendations for improving the treatment environment in Korea.

Question: What is the incidence of endometrial cancer in Korea?

Answer: Endometrial cancer is often referred to as a “developed country cancer” and has accounted for a high proportion of women's cancers in Western countries. However, in Korea, the incidence of endometrial cancer was the lowest among gynecologic cancers until the 2000s, when cervical cancer was the most common, followed by ovarian cancer and endometrial cancer. However, over the past 20 years, the incidence of endometrial cancer has more than tripled due to a sharp increase in the number of cases, and last year it became the most common gynecologic cancer.

Currently, about 10,000 gynecologic cancers are diagnosed in Korea each year, of which endometrial cancer has increased to more than 4,000, while the number of cervical cancer cases has decreased to about 2,000. While the incidence of ovarian cancer has remained relatively stable without significant changes, the increase in endometrial cancer has been significant.

Q: What is the prognosis of endometrial cancer, and how do the characteristics of its two major types differ?

A: Endometrial cancer is generally considered to have a good prognosis. This is because the lining of the uterus is where periods are produced, so when cancer develops, blood vessels are drawn to the area, and bleeding occurs relatively quickly. Patients who experience this type of abnormal bleeding tend to seek medical attention early, which is why it's one of the most diagnosed gynecologic cancers. Endometrial cancer is also relatively slow to progress and is often highly treatable.

However, not all endometrial cancers have a good prognosis. Certain types of endometrial cancer have a relatively poor prognosis and need to be recognized. Endometrial cancer can be divided into two main types: Type 1 and Type 2.

Type 1 is closely related to lifestyle factors, such as obesity and a Westernized diet, and responds well to treatment and generally has a good prognosis. Type 2, on the other hand, is independent of lifestyle, occurs primarily in older adults, and is often difficult to treat. Traditionally, endometrial cancer has been classified into these two types for the past 40 years, and while an increase in Type 1 endometrial cancer was expected in Korea as dietary habits became more Westernized, national data shows that Type 2 is also increasing. The exact cause of this is still unknown.

The increase in Type 2 is important because it is a key factor in determining the overall prognosis of endometrial cancer. Type 1 can be cured with surgery in most cases, so the increase in incidence doesn't significantly impact patient survival rates if treated well. However, Type 2 endometrial cancer is much more difficult to treat. Even if the visible tumor is surgically removed, there is a high likelihood that microscopic lesions have spread, making systemic therapy essential.

In addition, the majority of endometrial cancer recurrences occur in Type 2, and once it recurs, it is very difficult to cure. Therefore, the increase in Type 2 patients is likely to worsen the overall survival rate of endometrial cancer.

This is a trend in Korea and the world, and the prevailing view is that endometrial cancer mortality rates will increase further in the future. Amid these changes, the paradigm of endometrial cancer treatment is also shifting toward Type 2, and new drug development is focusing on therapies targeting Type 2 endometrial cancer.

Q: You mentioned the importance of systemic therapy. Recently, immuno-oncology agents, in addition to conventional chemotherapy, have become the standard of care for first-line treatment in advanced or recurrent patients. What is the rationale behind this?

A: The NRG-GY018 study of pembrolizumab (Keytruda in trademark) and the RUBY study of dostalimumab are two of the most important clinical studies demonstrating the effectiveness of immuno-oncology in the treatment of endometrial cancer. The two studies coincidentally started around the same time in the U.S. and Europe, and their results were published around the same time. Both studies consistently found that immuno-oncology combinations produced better outcomes than conventional chemotherapy alone.

Both studies confirmed the effectiveness of immuno-oncology across the entire patient population, including both MMRd (mismatch repair defective) and MMRp (mismatch repair preserved) patients, with a much stronger treatment effect in the MMRd group. This was a common finding in both studies, suggesting that the combination of immuno-oncology with conventional chemotherapy may improve survival and reduce the risk of disease progression and death in patients with advanced or recurrent endometrial cancer.

Notably, the RUBY study of dostalimumab analyzed progression-free survival (PFS) in the dMMR/MSI-H population and found a hazard ratio (HR) of 0.28, which was not only statistically significant but also clinically compelling, indicating a very strong treatment effect. These numbers are rarely seen in clinical studies and strongly suggest that immuno-oncology may be an innovative treatment option for dMMR/MSI-H patients.

Q: However, no immuno-oncology drugs are reimbursed for first-line treatment in Korea. What are the real-world implications?

A: When new drugs are introduced in clinical practice, the financial burden is one of the most difficult things for clinicians to explain to patients. It's important to determine how meaningful the medical benefit of a new treatment is relative to its cost, which is an important factor in helping clinicians decide on treatment options.

For example, in MMRd patients, immuno-oncology treatment provides an overwhelmingly high therapeutic benefit, so clinicians may decide it is worth the financial burden and strongly recommend it. In contrast, for MMRp patients, the benefits of immuno-oncology are relatively limited, and careful explanation is needed to weigh the expected benefits and economic burden of treatment. A cautious approach is required in this process, as there is a risk of overtreatment if healthcare providers recommend immuno-oncology in an overly strong tone.

Furthermore, there is no single standard of care; instead, there is a range of treatment options based on guidelines. In clinical practice, if an MMRp patient asks for “the most effective treatment without considering the cost,” a healthcare provider may naturally prescribe an immuno-oncology drug. Conversely, for patients with a high financial burden, there is no absolute standard of care (Invariant Treatment), as there are examples of patients surviving without relapse with conventional chemotherapy alone.

However, for patients with MMRd, the difference in effectiveness between immuno-oncology and conventional chemotherapy is so great that it may not be medically or ethically appropriate to recommend this treatment for economic reasons. Thus, for MMRd patients, immuno-oncology is becoming a de facto standard of care, and it would be a departure from sound treatment principles for healthcare providers to exclude it.

Q: Two immuno-oncology drugs are currently available for first-line treatment -- Keytruda and Jemperli. Are there differences between the two treatments?

A: Typically, when two agents with the same mechanism of action are developed, clinical trials for each drug are conducted independently, which limits direct comparisons. However, based on a comprehensive review of the clinical data published to date, there does not appear to be a significant difference in the two drugs' overall effectiveness and safety profile.

However, differences in the patient populations recruited in each trial can be considered. For example, while most studies were conducted in high-risk endometrial cancer patients, dostalimumab (RUBY) included certain cell subtypes, whereas pembrolizumab (NRG-GY018 study) excluded them. Therefore, if an endometrial cancer patient has a specific cell subtype, such as clear cell carcinoma or carcinosarcoma, dostalimumab, which has clinical data that includes this patient population, maybe a more appropriate choice.

However, patients with these specific cell subtypes represent only 1-2 percent of the population, leaving the question of which immuno-oncology agent to choose for most endometrial cancer patients.

In addition, one of the most important factors in evaluating immuno-oncology agents is the clinical trial's primary endpoint. Even if a treatment appears clinically effective, its value may be limited if it fails to produce statistically significant results. For example, a favorable survival curve and low hazard ratio may not qualify as a statistically significant treatment effect if it fails to meet the statistical criteria set by the study.

In this regard, dostalimumab has two co-primary endpoints: overall survival (OS) and progression-free survival (PFS). On the other hand, Pembrolizumab only had a primary endpoint of PFS and did not demonstrate an improvement in OS. Since OS is traditionally considered the most important endpoint in evaluating anticancer drugs, dostalimumab is the only immuno-oncology drug that has improved OS.

However, when discussing the effectiveness of immuno-oncology drugs, it is also important to distinguish whether they are effective in the entire patient population or only in patients with specific biomarkers. Because the dostalimumab trial included MMRd and MMRp patients, the observed improvement in OS does not necessarily mean that it was effective in all patients. While most studies have shown that MMRd patients have a much stronger response to immuno-oncology, the pembrolizumab study analyzed MMRd and MMRp patients separately and statistically demonstrated an improvement in PFS for each.

Based on these findings, if OS improvement is a more important endpoint, MMRp patients are likely to choose dostalimumab. On the other hand, if patients trust the independently validated data in the MMRp population, they are more likely to choose pembrolizumab. In conclusion, there is no significant difference in the efficacy of the two drugs per se, but clinicians' choice may depend on the criteria used in clinical studies to demonstrate efficacy.

Q: What changes do you see immuno-oncology agents bringing to endometrial cancer treatment in the future?

A: Taxol-carboplatin chemotherapy has traditionally been the standard of care for endometrial cancer, and a randomized controlled trial (RCT) published in 2004 established it as the most effective treatment. However, in the 20 years since, no new treatment options have emerged, and the treatment paradigm has not changed significantly.

In this context, a molecular classification study based on taxol-carboplatin (TCA) data about 10 years ago hypothesized that MMRd patients would have a higher tumor burden and be more responsive to immuno-oncology drugs. Based on this, full-scale clinical trials were conducted, and immuno-oncology treatment was rapidly established, with much better-than-expected results.

Most importantly, the incidence of endometrial cancer has been increasing among younger patients. In younger patients, preserving fertility is an important treatment goal and hormonal therapy has traditionally been the only option for preservation. However, patients who do not respond to hormonal therapy eventually have to undergo a hysterectomy, which has the limitation of permanently destroying the patient's fertility.

Interestingly, when analyzing the group of patients who did not respond to hormonal therapy, a significant number of them were MMRd patients. This suggests the possibility of using immuno-oncology as an alternative to hormonal therapy in MMRd patients for whom immuno-oncology works well, and studies are currently underway to explore this option. Initial data suggest that immuno-oncology may also positively affect fertility preservation. In addition, unlike cytotoxic anticancer drugs, immuno-oncology drugs are unlikely to have a significant impact on ovarian function, making them an effective treatment option while protecting ovarian fertility.

Q: What would you say about the Korean treatment landscape?

A: In the past, Type 2 patients often relapsed within about a year and a half after receiving chemotherapy, and the average survival time was only two and a half years. This made the treatment process frustrating for patients and medical professionals. However, since the introduction of immuno-oncology, treatment outcomes have improved dramatically, and survival times have been extended beyond conventional treatments.

Notably, for MMRd patients, immuno-oncology treatment has reached a point where the possibility of a cure can even be discussed. This breakthrough has completely changed the treatment paradigm and marks a decisive turning point in the treatment of endometrial cancer.

Nowadays, even a one-year delay in cancer diagnosis is associated with an increased survival rate, which means that the pace of drug development is rapid, and the number of effective drugs is increasing rapidly. In addition, when existing drugs are covered by insurance, patients have greater access to the best treatments with less financial burden. Therefore, it is important to speed up the reimbursement process for proven therapies to reach more patients as quickly as possible.