One article summarizes the research progress of three major gynecological tumor immunotherapy

Introduction Endometrial cancer, cervical cancer and ovarian cancer are the three most common gynecological malignancies
.

The current treatments for these gynecological tumors are mainly surgery, chemotherapy, radiotherapy, and targeted therapy, but there is a high proportion of patients with recurrence or metastasis after surgery, as well as adverse drug reactions or multi-drug resistance
.

As the research of immune checkpoint inhibitor (ICI) in the field of tumor treatment continues to deepen, there is still a lot of room for development in its clinical application in gynecological tumors
.

About 70% of endometrial cancers are confined to the uterus at the time of diagnosis, which is an early clinical stage with a good prognosis
.

However, the recurrence rate of patients with advanced endometrial cancer is high, reaching 66.
7%, the prognosis is poor, and the survival period is short.
The 5-year survival rate is only 16%
.

Studies have found that the expression ratio of PD-1/PD-L1 in endometrial cancer is relatively high.
Among them, the expression rate of endometrioid adenocarcinoma is 40%～80%, serous carcinoma is 10%～68%, clear cell carcinoma It is 23%～69%
.

At the same time, endometrial cancer is also a tumor with a higher incidence of MSI-H and/or dMMR, up to 31.
37%, and TMB-H accounts for 11.
2%
.

Advanced/recurrent endometrial cancer is a gynecological tumor that benefits more from ICI treatment
.

The current evidence for the application of ICI to advanced/recurrent endometrial cancer comes from the KEYNOTE series of clinical trials of pembrolizumab (KEYNOTE-016, KEYNOTE-158, KEYNOTE-028)
.

Data show that pembrolizumab should be used in patients with advanced or recurrent endometrial cancer who have received at least one standard chemotherapy and the objective response rate (ORR) of MSI-H/dMMR patients is 53.
0%～57.
1%, TMB- The ORR of H patient was 46.
7%, while the ORR of PD-L1 positive patients was 13%
.

The Z1D subgroup of the NCI-MATCH study aims to evaluate the efficacy of nivolumab in the treatment of dMMR patients with non-colorectal tumors
.

This subgroup included a total of 17 cases of endometrioid adenocarcinoma, endometrioid adenocarcinoma with other pathological types, and carcinosarcoma, of which 13 cases were endometrioid adenocarcinoma patients, with an ORR of 45.
4%; 3 cases had a complete remission (CR) 2 cases were endometrioid adenocarcinoma
.

Cohort A1 of the GARNET study was designed to evaluate the efficacy of dostarlimab-gxly in patients with dMMR endometrial cancer who progressed or recurred after platinum-containing treatment.
The results showed that the ORR was 44.
7% and the disease control rate (DCR) was 57.
3%
.

These studies further support the use of PD-1 monoclonal antibody for MSI-H/dMMR advanced/recurrent endometrial cancer patients who have received previous treatment
.

Immune combination In endometrial cancer, there have been preliminary research results of immune combination with anti-angiogenic tyrosine kinase inhibitor (TKI)
.

The KEYNOTE-146 study is a phase Ib/II, multicenter, open-label, single-arm study, which aims to evaluate the use of pembrolizumab combined with lenvatinib for advanced stages that have previously received no more than second-line chemotherapy and have measurable lesions For the efficacy and safety of endometrial cancer patients, the 24-week ORR of the primary study endpoint was 38.
0%; the ORR of non-MSI-H/dMMR patients was 37.
2%, and the ORR of MSI-H/dMMR patients was 63.
6%
.

For patients who have previously received treatment, regardless of MSI status, the median duration of response (DOR) is 21.
2 months, the median progression-free survival (PFS) time is 7.
4 months, and the median overall survival (OS) time is 16.
7 Months
.

The results of the study showed that the combined regimen for the treatment of recurrent endometrial cancer not only has a significant efficacy in MSI-H patients, but also has a better efficacy in MSS patients than pembrolizumab single-agent therapy
.

The KEYNOTE-775 study is a multi-center, open-label, randomized controlled phase III clinical study that compared pembrolizumab combined with lenvatinib with the treatment regimen selected by the doctor (doxorubicin or paclitaxel weekly therapy) for Efficacy and safety of patients with advanced/recurrent endometrial cancer who have received at least first-line platinum-containing drugs in the past
.

The results showed that compared with the treatment options selected by doctors, pembrolizumab combined with lenvatinib treatment prolonged the median PFS time of patients with normal mismatch repair protein function (pMMR) by 2.
8 months, and reduced the risk of recurrence or death by 40%; The median OS time was extended by 5.
4 months, and the risk of death was reduced by 32%; ORR was increased by 15.
2%
.

For the overall patient population, the median PFS time was extended by 3.
4 months, and the risk of recurrence or death was reduced by 44%; the median OS time was extended by 6.
9 months, and the risk of death was reduced by 38%; ORR was increased by 17.
2%
.

The study shows that in patients with advanced/recurrent endometrial cancer who have previously received at least first-line platinum-containing drug treatment, pembrolizumab combined with lenvatinib can improve the prognosis of all patients, including pMMR
.

Based on the above research evidence, pembrolizumab combined with lenvatinib is recommended for non-MSI-H/dMMR advanced/recurrent endometrial cancer
.

Cervical cancer The treatment of relapsed/refractory cervical cancer has always been a difficult point in clinical practice for a long time, and the curative effect needs to be improved urgently
.

The proportion of MSI-H in cervical cancer patients is low (2.
62%), but the proportion of TMB-H is 14.
9%, and the expression rate of PD-L1 is higher, reaching 34.
4%-96.
0%, suggesting that PD-1 inhibitors have It may be used for the treatment of advanced/recurrent cervical cancer
.

According to the data of patients with advanced/recurrent cervical cancer included in the KEYNOTE series of studies, the ORR of patients with PD-L1 positive expression for pembrolizumab treatment is 14.
6%-17.
0%
.

In addition, the results of several phase I/II clinical studies have shown that nivolumab also has a certain effect in the treatment of advanced/recurrent cervical cancer, with an ORR of 4.
0% to 26.
3%
.

Both the KEYNOTE-158 and JapicCTI-163212 studies performed subgroup analysis based on the PD-L1 expression status of the included cases, and the results showed that PD-L1 positive expression patients had better responsiveness to PD-1 inhibitors
.

The EMPOWER-Cervical1/GOG-3016/ENGOT-cx9 study is a comparison between cemiplimab and the chemotherapy regimen selected by the doctor (pemetrexed, vincristine, topotecan, irinotecan or gemcitabine) in the treatment of the progress of previous first-line platinum-based chemotherapy A multi-center, open-label, randomized controlled phase III clinical study of patients with advanced or metastatic cervical cancer
.

The interim analysis showed that in the overall population, compared with the chemotherapy group, patients in the cemiplimab group had a significantly longer PFS time and a 25% reduction in the risk of recurrence or death; OS time was significantly extended by 3.
5 months and a 31% reduction in the risk of death
.

The ORR of patients in the Cemiplimab group was 16%, and the median duration of response was 16 months; the ORR of patients in the chemotherapy group was 4%, and the median duration of response was 7 months
.

In the squamous cell and adenocarcinoma subgroups, the trend is consistent with the general population: the prognosis of patients in the cemiplimab group was significantly improved
.

The study showed that, compared with single-agent chemotherapy, cemiplimab can significantly improve the OS of advanced or metastatic cervical cancer patients who have progressed from previous first-line platinum-containing chemotherapy, regardless of the PD-L1 expression status and histological type
.

Immunization Combination Currently, clinical trials of immunotherapy combined with chemotherapy/radiotherapy, PARP inhibitors, and small molecule TKIs for the treatment of cervical cancer are underway
.

The KEYNOTE-826 study is a randomized, double-blind, placebo-controlled phase III clinical study that explores the application of pembrolizumab combined with platinum-containing chemotherapy (with or without bevacizumab) for persistent, recurrent or Efficacy and safety of first-line treatment for patients with metastatic cervical cancer
.

The results of the study showed that compared with the control group, regardless of the expression status of PD-L1 [CPS ≥ 1%, CPS ≥ 10%, Intention-to-treat (ITT) population], Pembrolizumab + chemotherapy ± bevacizumab Both can significantly increase the patient's PFS (P<0.
001) and reduce the risk of death
.

Similarly, pembrolizumab combined with chemotherapy ± bevacizumab can also significantly increase the patient's OS (P<0.
001), regardless of PD-L1 status
.

This program is expected to become the new standard for the first-line treatment of advanced recurrence and metastatic cervical cancer
.

Most ovarian cancers are serous epithelial ovarian cancer.
MSI-H cases are rare, with only 1.
37% reported, TMB-H cases accounting for 1.
47%, and PD-L1 expression cases accounting for 10%-30%
.

Currently, the scope of application of immunotherapy in ovarian cancer is limited
.

Most of the clinical trials of immune single-agent ICI single-agent treatment of ovarian cancer are in phase I to II.
For patients with advanced/recurrent ovarian cancer, the overall response rate is not high.
Current data show that the ORR is 5.
9% to 22.
2%
.

The NINJA study and the JAVELIN Ovarian 200 study suggested that compared with chemotherapy, the application of ICI alone did not improve the prognosis of patients
.

Based on the approved dMMR/MSI-H and TMB-H pantumoma indications of pembrolizumab, only pembrolizumab is recommended for the treatment of patients with recurrent ovarian cancer with dMMR/MSI-H or TMB-H
.

Immunization combined with ICI monotherapy is not effective in the treatment of ovarian cancer.
Some studies have explored the mode of ICI combined with chemotherapy
.

The JAVELIN Ovarian 100 study explored the efficacy of first-line paclitaxel + carboplatin chemotherapy combined with avelumab and maintenance therapy in newly treated patients with ovarian cancer.
The results showed that compared with chemotherapy alone, the combination of avelumab and maintenance therapy did not benefit patients with PFS time , The study was discontinued early
.

For platinum-resistant recurrent ovarian cancer, some studies of combined chemotherapy suggest that compared with previous single-agent therapy, combined therapy has a certain degree of improvement in ORR, but the response time is shorter
.

The Phase III JAVELIN Ovarian 200 study showed that the combination therapy had no significant additional benefit
.

Based on these studies, for patients with ovarian cancer, it is not enough to recommend the clinical application of PD-1/PD-L1 inhibitors combined with chemotherapy
.

ICI combined with targeted drugs currently has only phase I to II research results, and the overall ORR is 15% to 32%
.

In the study of ICI combined with PARP inhibitors, the ORR of MEDIOLA in patients with gBRCA mutation and platinum-sensitive ovarian cancer with olaparib combined with duvalizumab was 71.
9%, but in niraparib combined with pembrolizumab The ORR in the TOPACIO/KEYNOTE-162 study applied to platinum-resistant ovarian cancer patients was only 18%
.

The NRG GY003 study used a dual-immune combination therapy.
Compared with nivolumumab alone, the ORR of nivolumab combined with ipilimumab in the treatment of ovarian cancer patients was significantly increased (31.
4% vs 12.
2%, P = 0.
034), the median PFS was significantly prolonged (3.
9 months vs 2.
0 months, P=0.
004), and the median OS time was prolonged, but the difference was not statistically significant (28.
1 months vs 21.
8 months, P=0.
43)
.

Based on the above studies, although PD-1/PD-L1 inhibitors combined with certain targeted drugs have shown certain efficacy, more research evidence is still needed, and it is not enough to recommend clinical applications
.

Summary Immunotherapy has shown a certain clinical effect on some patients with gynecological malignant tumors, and is currently mainly used for advanced and recurrent patients who have failed conventional treatment
.

Among the three major gynecological malignancies, endometrial cancer has the better effect, followed by cervical cancer, and ovarian cancer has the worst effect
.

With ICI treatment, it is very important to screen the population with advantages in treatment
.

At present, ICI monotherapy has limited clinical efficacy in the treatment of gynecological tumors, and its combined treatment with chemotherapy, anti-angiogenesis therapy, and PARP inhibitors is expected to improve the efficacy
.

Reference: Chinese Medical Association Gynecological Oncology Branch.
Guidelines for clinical application of immune checkpoint inhibitors in gynecological tumors [J].
Chinese Journal of Medical Frontiers (Electronic Edition), 2021, 13(9): 1-24.
How to obtain the above guide? 1.
Click on the mini program below and directly search for the corresponding guide to read the PDF version: 2.