Exploration of molecular classification of endometrial cancer for immunotherapy in advanced-stage patients.

Background

In the past decade, a significant advancement in the diagnosis and treatment of endometrial cancer has been the development of a molecular classification system. Molecular features contribute to understanding the risk of recurrence and survival outcomes. The use of molecular detection methods classifies endometrial cancer into four distinct molecular categories: POLE ultramutated type (POLEmut), microsatellite instability or mismatch repair-deficient type (MSI-H or MMRd), nonspecific molecular profile type (NSMP), and p53 abnormal type (p53abn). Each category corresponds to a different prognosis, with POLEmut generally having the best prognosis, p53abn having the poorest prognosis, and the remaining two categories having intermediate prognoses. Molecular classification has been incorporated into clinical guidelines (NCCN, CSCO, etc.) and the latest FIGO staging. Molecular classification detection methods include NGS (comprehensive typing), immunohistochemistry (MMR protein, p53 protein), Sanger sequencing (POLE hotspot mutations), and fragment analysis (MSI). Regardless of the method used for detection, each has its own unique advantages.

Endometrial cancer molecular classification detection process[1]

Proportion and prognostic characteristics of patients with different subgroups

Both MMR and MSI are biomarkers for predicting the efficacy of immunotherapy. Therefore, NCCN guidelines recommend the use of single-agent immune checkpoint inhibitors for recurrent endometrial cancer with mismatch repair deficiency (MMRd). However, the efficacy of immunotherapy as a single agent for MMRd endometrial cancer is not "remarkable," with an average overall response rate (ORR) of only 45%.

Summary of data from different studies

Advanced and recurrent endometrial cancer first-line treatment new research

This year at ESMO, the GY018 and RUBY studies explored new treatment approaches for first-line therapy in advanced or recurrent endometrial cancer. The two studies had slightly different patient populations. The GY018 study included patients with measurable stage III/IVA or measurable/unmeasurable stage IVB or recurrent endometrial cancer. In contrast, the RUBY study enrolled patients with measurable lesions in stages IIIA-IIIC1 at initial treatment, no evaluable lesions in initial treatment for cancer sarcoma, clear cell carcinoma, or mixed histology, and stages IIC2-IV with no evaluable lesions or recurrent endometrial cancer.

In the GY018 study, as of the data analysis cutoff, the median follow-up time in the dMMR (mismatch repair-deficient) cohort was 12 months. The progression-free survival (PFS) rate was 74% in the pembrolizumab monotherapy group compared to 38% in the placebo group. The median PFS was not reached (NR) in the pembrolizumab group versus 7.6 months in the placebo group. Pembrolizumab monotherapy reduced the risk of disease progression and death by 70% (HR 0.30; 95% CI, 0.19-0.48; P<0.001).

In the pMMR (mismatch repair-proficient) cohort with a median follow-up time of 7.9 months, the median PFS was 13.1 months versus 8.7 months for the pembrolizumab monotherapy and placebo groups, respectively. Pembrolizumab monotherapy reduced the risk of disease progression and death by 46% (HR 0.54; 95% CI, 0.41-0.71; P<0.001).

GY018 study result[2]

From the perspective of RUBY research, as of the data analysis, in the dMMR/MSI-H queue, the PFS rate of the dostarlimab group is 61.4%, while the placebo group is 15.7%. Dostarlimab reduces the risk of disease progression and death in patients by 72% (HR 0.28; 95% CI, 0.16-0.50; P<0.001); the OS rates are 83.3% vs 58.7%, and dostarlimab reduces the risk of patient death by 70% (HR 0.30; 95% CI, 0.33-0.70).

In the pMMR queue, the median PFS rates for the two groups are 28.4% vs 18.8%, and dostarlimab reduces the risk of disease progression and death in patients by 24% (HR 0.76; 95% CI, 0.59-0.98); the OS rates are 67.7% vs 55.1%, and dostarlimab reduces the risk of patient death by 27% (HR 0.73; 95% CI, 0.52-1.02).

RUBY study result[3]

However, there are still uncertainties regarding whether patients with other subtypes can also benefit from immunotherapy. Therefore, the RUBY study conducted further analysis on patients with other subtypes as well. In the first part of the RUBY study, molecular classification was performed on the whole exome sequencing (WES) results of all enrolled patients. Analysis was conducted on 400 out of 494 patients (400/494). The results showed that in the POLE mutation subgroup, patients had a good prognosis with no recurrence or death, suggesting that observation could be considered. In the dMMR/MSI-H subgroup, immunotherapy significantly improved progression-free survival (PFS) and overall survival (OS), reducing the risk of recurrence and death by approximately 70%. Similarly, in the P53 mutation subgroup, immunotherapy also significantly improved PFS and OS. In the NSMP (non-specific molecular profile) subgroup, the impact of immunotherapy on PFS and OS was not significant. Therefore, based on the clinical results from the RUBY study, patients with late-stage, recurrent, and metastatic dMMR/MSI-H and P53 mutation subtypes can greatly benefit from immunotherapy, while the benefits for other subtypes are not significant.

PFS according to molecular classification[4-5]

OS according to molecular classification[4-5]

Summary

Immunotherapy is playing an increasingly important role in endometrial cancer, providing numerous critical opportunities for the treatment of advanced endometrial cancer patients. For MSI-H/dMMR endometrial cancer patients, immunotherapy enhances the precision of endometrial cancer treatment. For MSS/pMMR endometrial cancer patients, immunotherapy, in combination with other treatments, secures treatment opportunities for more patients and opens up new avenues for treatment. In the future, emerging biomarkers such as TMB may bring more opportunities for immunotherapy in endometrial cancer. With the widespread exploration of immunotherapy, targeted therapy, and other approaches in gynecological tumors, the trend towards precision and individualized treatment is reshaping the landscape of gynecological tumor diagnosis and treatment. It is anticipated that in the near future, gynecological diagnosis and treatment will continue to optimize and improve, achieving more breakthroughs in the diagnosis and treatment of endometrial cancer.

References

[1]NCCN Uterine Tumor Diagnosis and Treatment Guidelines 2024.v1

[2]N Engl J Med. 2023 Jun 8;388(23):2159-2170.

[3]N Engl J Med. 2023 Jun 8;388(23):2145-2158.

[4]https://clinicaltrials.gov/ct2/show/NCT03981796.

[5]Mirza MR, et al. 2023 ESMO 740MO.

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