Pembrolizumab After Surgery for dMMR-Positive Endometrial Cancer

Endometrial (uterine) cancer, is the most common gynecological cancer in women. In recent years, both its incidence and mortality rates have also increased.

More effective treatment strategies are needed to prevent recurrence in patients with endometrial cancer who remain at high risk of recurrence despite early diagnosis and surgery.

In recent years, immunotherapieshave delivered groundbreaking results in endometrial cancer treatment. In approximately 30% of endometrial cancers, the tumors are mismatch repair deficient (dMMR) and immunotherapy has become a promising treatment option for patients with these tumors.

The Importance of dMMR and How It Is Tested

Mismatch repair deficient (dMMR)refers to a defect in the repair mechanism that corrects mismatches arising during DNA replication. dMMR causes DNA errors to accumulate in cells and leads to genetic instability, contributing to cancer development. This feature occurs particularly in colorectal, endometrial and certain other cancers and is an important biomarker for immunotherapies.

dMMR Testing Methods:

dMMR status can be established using different methods that assess the function of DNA repair mechanisms in tumors:

1. Immunohistochemistry (IHC):

   • Used to examine MMR proteins (MLH1, MSH2, MSH6, PMS2).
   • Loss of MMR proteins indicates dMMR.
   • IHC is a widely used, rapid and economical method.

2. Microsatellite Instability (MSI) Testing:

   • Measures variability in microsatellite regions.
   • Performed using PCR and sequencing methods.
   • High MSI (MSI-H) generally indicates the presence of dMMR.

3. NGS (Next-Generation Sequencing):

   • Provides comprehensive gene-level analysis.
   • Can confirm MMR gene mutations and losses.
   • Frequently used for research purposes and advanced genomic studies.

Immunohistochemistry (IHC)is considered the most commonly used method for detecting dMMR in clinical practice. If IHC identifies positivity or loss, MSI testing can be used for confirmation.

Thus, IHC is generally the first choice, while additional methods such as MSI testing or NGS may be used in some situations to establish a definitive diagnosis.

Adjuvant Pembrolizumab for High-Risk, dMMR-Positive Endometrial Cancer: Findings From KEYNOTE-B21

This article discusses findings from the study known as KEYNOTE-B21 (GOG-3053/ENGOT-en11), presented at the 2024 International Gynecologic Cancer Society Meeting. In patients with newly diagnosed, high-risk endometrial cancer, the study examined pembrolizumab + adjuvant chemotherapy ± radiotherapy.

KEYNOTE-B21 Study Design

Objective: To investigate the effects of adjuvant pembrolizumab (a PD-1 inhibitor), administered with chemotherapy ± radiotherapy, on preventing recurrence and on survival in patients with high-risk, dMMR endometrial cancer.

Eligibility Criteria:

• High-Risk Endometrial Cancer: Serous or clear-cell histology, stage 3-4a disease, or p53 mutation-positive stage 1 disease.
• Patients who had undergone surgery with curative intent and had no residual disease after surgery were included in the study.

Method:

The decision on whether to administer radiotherapy was left to the investigator's discretion.

All patients received either placebo or pembrolizumab together with adjuvant chemotherapy (carboplatin + paclitaxel).

Primary Outcomes: Progression-free survival (PFS) and overall survival (OS) were evaluated in all participants and in the dMMR subgroup.

Study Findings

All Participants:

• Overall study results were reported as negative in the entire patient population.
• No significant difference in PFS was observed between the placebo and pembrolizumab groups (HR: 1.02).

dMMR Subgroup:

• In patients with dMMR tumors, adding pembrolizumab produced a significant improvement in progression-free survival.
• In this group, adding pembrolizumab reduced the risk of cancer progression by 69% (HR: 0.31, demonstrating a clear advantage over the placebo group).

• This result was consistent with findings in the dMMR subgroups of earlier immunotherapy studies (GY018, RUBY, AtTEnd, DUO-E).

Side Effects and Quality of Life:

• No new safety signal was observed in the pembrolizumab group compared with chemotherapy.
• Quality-of-life analyses found no significant difference between the groups.

Statistical Limitations:

• Although findings in the dMMR subgroup came from a prespecified analysis, no alpha was allocated to this analysis. Nevertheless, the clinical meaningfulness of the results was emphasized.

Clinical Interpretation of the Results

Use in the dMMR Population: Pembrolizumab shows promise as an adjuvant treatment for patients with high-risk endometrial cancer with dMMR tumors. These findings suggest that immunotherapy could become part of standard care in this specific subgroup.

• NCCN and FDA Approvals: Whether the study findings will be incorporated into NCCN guidelines and receive FDA approval remains an important question.

Future Research Areas

1. Eliminating Chemotherapy: Investigating the effects of immunotherapy alone as an adjuvant treatment in the dMMR population.
2. Pembrolizumab Alone: Extending data from studies such as KEYNOTE-C93 to applications in the adjuvant setting.
3. Long-Term Follow-Up: Assessing the long-term effects of pembrolizumab on preventing recurrence.

Conclusion

KEYNOTE-B21 demonstrated that adjuvant pembrolizumab significantly improved progression-free survival in patients with high-risk, dMMR endometrial cancer. These findings suggest that immunotherapy could become part of standard care for this population. However, the negative results in the ITT population highlight the need for further investigation of treatment strategies in other subgroups.