Professor Wu Xiaohua: Annual Progress of Cervical Cancer Diagnosis and Treatment in 2021

Zhu Jun, Wu Xiaohua (Department of Gynecologic Oncology, Fudan University Cancer Hospital, Shanghai)

In 2021, although the novel coronavirus pneumonia epidemic will continue, it will not stop the research and progress of anti-tumor therapy
.

At present, cervical cancer is still one of the most common malignant tumors in women worldwide, and its incidence is second only to breast cancer ,Colorectal cancer and lung cancer , ranked 4th

breast cancerColorectal Cancer Lung Cancer Screening Immunization

01 The value of adjuvant chemotherapy after concurrent chemoradiotherapy for locally advanced cervical cancer

01 The value of adjuvant chemotherapy after concurrent chemoradiotherapy for locally advanced cervical cancer 01 The value of adjuvant chemotherapy after concurrent chemoradiotherapy for locally advanced cervical cancer

Since the 1990s, cisplatin-sensitized concurrent chemoradiotherapy has been the standard treatment modality for locally advanced cervical cancer, with a 5-year survival rate of 60% to 66% for such patients
.

However, some patients develop local or distant metastases even after standard chemoradiotherapy

The findings, presented at the 2021 American Society of Clinical Oncology ( ASCO ) annual meeting, drew widespread attention
.

For patients with locally advanced cervical cancer, can concurrent chemoradiotherapy followed by adjuvant chemotherapy prolong the time to recurrence and OS? The OUTBACK study provided negative results for the efficacy of concurrent chemoradiotherapy followed by adjuvant chemotherapy for locally advanced cervical cancer

ASCO

A total of 926 patients were recruited from April 2011 to June 2017, and 919 patients were eligible for inclusion and included in the preliminary analysis: 463 in the ACT group and 456 in the control group
.

In the ACT group, 361 patients (78%) received ACT treatment with a median follow-up time of 60 months (IQR: 45-65 months)

Within 1 year of randomization, 81% of patients receiving ACT in the ACT group experienced grade 3 to 5 adverse events compared with 62% in the control group
.

More than 1 year after randomization, patients with grade 2 peripheral ACT than the incidence of neurotoxicity and the control group (7% :2%), other adverse events showed no statistical significance

statistics

Image credit: ASCO 2021

02 Changes in first-line treatment patterns for advanced, recurrent or metastatic cervical cancer

02 Changes in first-line treatment patterns for advanced, recurrent or metastatic cervical cancer02 Changes in first-line treatment patterns for advanced, recurrent or metastatic cervical cancer

For cervical cancer patients with initial recurrence or metastasis after standard treatment, the treatment options are limited, the overall survival rate is low, and the 5-year survival rate is about 17%.
Previous guidelines recommend chemotherapy (combined with bevacizumab) as their first-line treatment regimens, but chemotherapy combined with bevacizumab has limited efficacy
.

Therefore, finding new and effective treatments can bring new hope to these patients

guide

The results of the KEYNOTE-826 study reported at the 2021 ESMO Annual Meeting [2] make the combination therapy mode of pembrolizumab plus chemotherapy ± bevacizumab expected to become a new standard for persistent, recurrent or metastatic cervical cancer treatment options
.

According to the existing guidelines, platinum-containing chemotherapy is the standard treatment for persistent, recurrent or metastatic cervical cancer, and the results of the phase II study KEYNOTE-158 showed that pembrolizumab treatment received ≥1 line of chemotherapy, programmed death The objective response rate (ORR) of patients with recurrent or metastatic cervical cancer positive for protein ligand-1 (PD-L1) was 14.

The KEYNOTE-826 study is a randomized, double-blind, phase III study of pembrolizumab combined with chemotherapy versus placebo combined with chemotherapy in the treatment of persistent, recurrent or metastatic cervical cancer.
Persistent, recurrent or metastatic cervical cancer who has not received systemic chemotherapy (radiotherapy or chemoradiotherapy is allowed)
.

Subjects were randomized 1:1 to the experimental group (pembrolizumab plus chemotherapy ± bevacizumab) and the control group (placebo plus chemotherapy ± bevacizumab)

The KEYNOTE-826 study is a pivotal study of pembrolizumab combined with chemotherapy for first-line treatment of advanced, recurrent or metastatic cervical cancer.
A major progress and breakthrough
.
At the same time, the KEYNOTE-826 study also provides further support for the use of immunotherapy for the first-line treatment of advanced, recurrent, and metastatic cervical cancer
.
This study further provides strong evidence-based medical evidence for the role of immunotherapy in recurrent and metastatic cervical cancer, which has advanced the application of immunotherapy
.

Image credit: ESMO 2021

03 New options for second-line treatment of advanced, recurrent or metastatic cervical cancer

03 New options for second-line treatment of advanced, recurrent or metastatic cervical cancer03 New options for second-line treatment of advanced, recurrent or metastatic cervical cancer

In the second-line treatment of advanced, recurrent or metastatic cervical cancer, chemotherapy is the main treatment recommended in previous domestic and foreign guidelines, but the efficacy is limited
.
Thanks to the prominent role of immunotherapy in the second-line treatment of cervical cancer, the National Comprehensive Cancer Network (NCCN) guidelines also recommend that immunotherapy can be used for advanced and recurrent cervical cancer.
, The mainstream direction of clinical treatment of recurrent cervical cancer
.
Although a number of studies such as KEYNOTE-028 and Checkmate-358 have suggested the effectiveness of immunotherapy single drug in the treatment of cervical cancer, the overall response rate and other survival data are slightly weak.
Therefore, more and more clinical trials have begun to explore different drugs.
The role of the combination in the second-line treatment of advanced, recurrent or metastatic cervical cancer also kicked off the 2.
0 era of cervical cancer immunotherapy
.

The EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study, reported at the 2021 ESMO Annual Meeting, compared cemiplimab with investigator's choice (IC) in patients with recurrent/metastatic (R/M) cervical cancer ) chemotherapy phase III trial results provide a new solution for the second-line treatment of R/M cervical cancer, the drug can significantly improve the OS of R/M cervical cancer patients after first-line treatment, cemiplimab is expected to be included in the second-line treatment [3]
.

This study is an open, randomized, multicenter Phase III clinical study
.
Subjects were patients with R/M cervical cancer who had progressed after previous platinum-containing first-line therapy, regardless of PD-L1 expression status or histological type
.
Randomized according to the ratio of 1:1 into the cemiplimab group (anti-PD-1 cemiplimab treatment) and the control group (IC chemotherapy, chemotherapy regimens include pemetrexed, vinorelbine, gemcitabine, irinotecan or topotecan)
.
The primary endpoint of the study was OS
.
The interim analysis showed that the trial included 608 patients, 477 patients with cervical squamous cell carcinoma, and 131 patients with cervical adenocarcinoma
.
This is also the largest clinical study conducted in R/M cervical cancer
.
Compared with chemotherapy, the cemiplimab group had a 31% lower risk of death (HR=0.
69, one-sided P=0.
000 11), a 25% lower risk of disease progression (HR=0.
75, one-sided P=0.
00048), and ORR Significantly improved (16% vs 6%; one-sided P=0.
000 04)
.

Image credit: ESMO 2021

Data further stratified by pathological type showed that among patients with squamous cell carcinoma: the risk of death was reduced by 27% in the cemiplimab group, and the median survival was 11.
1 months, compared with 8.
8 months in the control group (238 patients) (HR= 0.
73; 95%CI: 0.
58-0.
91; one-sided P=0.
003 (06)
.
Patients in the cemiplimab group had a 29% lower risk of disease progression (HR = 0.
71; 95% CI: 0.
58 to 0.
86; one-sided P = 0.
000 26)
.
And compared with the control group, the ORR of the patients in the cemiplimab group was significantly improved (18%: 7%)
.
Similarly, among patients with adenocarcinoma: a 44% lower risk of death in the cemiplimab group and a median survival of 13.
3 months compared with 7.
0 months in the chemotherapy group (66 patients) (HR = 0.
56; 95% CI: 0.
36- 0.
85; nominal one-sided P < 0.
005)
.
Compared with chemotherapy, patients in the cemiplimab group had a 9% lower risk of disease progression (HR = 0.
91; 95% CI: 0.
62-1.
34), and ORR was also improved (12%: 5%)
.
In terms of drug safety, no novel adverse reactions of cemiplimab were observed in this study
.
Drug-related adverse events occurred in 88% of patients in the cemiplimab group and 91% in the chemotherapy group
.
Thus, cemiplimab significantly improved OS in R/M cervical cancer patients with disease progression after platinum-containing first-line therapy compared with single-agent chemotherapy, regardless of the patient's PD-L1 expression status and histology, and No new adverse reactions were found
.

 

Image credit: ESMO 2021

Tisotumab vedotin (TV) is an antibody-drug conjugate (ADC) targeting tissue factor (TF).
Previous preclinical studies have found that TF is highly expressed in cervical cancer cells and can participate in Tumor growth, angiogenesis and metastasis
.
The innovaTV201 study shows that TV has better curative effect in a variety of cancer types
.
The 2021 European Society of Medical Oncology (ESMO) annual meeting reported the interim results of a phase II study of TV in the treatment of recurrent or metastatic cervical cancer (innova TV205/GOG-3024/ENGOT-cx8) [4], The study mainly included patients with recurrent or metastatic cervical cancer who had progressed after receiving standard treatment, and were divided into three study treatment groups, TV combined with bevacizumab (Arm A) or pembrolizumab (Arm B) or Carboplatin (Arm C), determine the maximum tolerated dose, and assess safety and tolerability
.
The efficacy and safety results of the first-line TV + carboplatin treatment cohort showed that the ORR was 18%, and the mPFS was 9.
5 months; the efficacy and safety results of the second-line/third-line TV + pembrolizumab treatment cohort showed that the ORR was 13%, and the mPFS was 9.
5 months.
5.
6 months
.
Safety analysis showed that most adverse reactions were grade 1 or 2, and there were no unexpected adverse events
.
Both the first-line treatment cohort of TV+carboplatin and the second-/third-line treatment cohort of TV+pembrolizumab showed encouraging antitumor activity, and the treatment prospects in patients with recurrent or metastatic cervical cancer are promising
.
These data support further studies to evaluate other combination regimens with the addition of TV as a treatment option for recurrent or metastatic cervical cancer.
A dose-expansion cohort study of TV+pembrolizumab first-line therapy is underway, and it is expected that further results will be available in the future.
Update
.

Blood vessel

The C550 study is a phase II study of balstilimab (PD-1 antibody) combined with zalifrelimab (CTLA-4 antibody) as a treatment for R/M cervical cancer patients [5].
of cervical squamous cell carcinoma, adenosquamous carcinoma and adenocarcinoma
.
Enrolled patients received balstilimab 3 mg/kg every 2 weeks in combination with zalifrelimab 1 mg/kg every 6 weeks
.
As of the result analysis, a total of 125 patients were eligible for efficacy analysis
.
The ORR of the overall patients was 25.
6%, including 10 patients who achieved CR and 22 patients who achieved PR
.
The median follow-up time of the study was 21 months, the mPFS time was 2.
7 months (95%CI: 1.
5-3.
7), and the mOS time was 12.
8 months (95%CI: 8.
8-17.
6); while the subgroup of PD-L1 positive patients The mOS time was 15.
7 months (95% CI: 7.
6 to 21.
1)
.
In terms of adverse reactions, most of the adverse reactions were grade 1 or 2, and there were no unexpected adverse events
.

This study is the largest to date evaluating the efficacy and safety of dual immune checkpoint inhibitors PD-1/CTLA-4 in R/M cervical cancer
.
The combination of balstilimab and zalifrelimab resulted in high and durable response rates, with satisfactory overall survival and good tolerability
.
In PD-L1-positive patients, balstilimab combined with zalifrelimab was more effective
.

Image credit: ESMO 2021

The phase II study of anlotinib combined with sintilimab in the treatment of patients with recurrent advanced cervical cancer [6] is a breakthrough in China's innovative drug in the field of tumor treatment
.
The prospective, multicenter, single-arm, phase II clinical study included subjects who had received at least first-line platinum-containing chemotherapy, histopathologically confirmed recurrent advanced cervical cancer (including squamous cell carcinoma, adenocarcinoma or adenocarcinoma) Squamous cell carcinoma), and histopathologically confirmed PD-L1 positive, ECOG 0-1 points
.
The received treatment regimen was: oral anlotinib (10 mg qd, days 1 to 14, 21 days as a cycle), and sintilimab intravenously (200 mg q3w)
.
Treatment continued until disease progression, death, or unacceptable toxicity
.
The primary endpoint was ORR, and secondary endpoints included disease control rate (DCR), PFS, OS, safety, and biomarkers
.
The results showed that a total of 39 patients were included in the efficacy evaluation group
.
Thirty-six (85.
7%) patients had an ECOG PS score of 1
.
In addition, 35 (83.
3%) patients had squamous cell carcinoma, 25 (59.
5%) patients had received prior 2 or 3 chemotherapy, and 39 (92.
9%) patients had prior radiation therapy
.
The median follow-up time of patients was 10.
9 months (0.
03-19.
2 months)
.
In the ITT population, 2 (4.
8%) patients achieved a CR and 21 (50%) patients achieved a PR; the confirmed ORR was 54.
8%
.
The median time to response was 1.
71 months
.
Furthermore, the DCR was 88.
1%
.
In the efficacy evaluation population, the ORR was 59% and the DCR was 94.
9%
.
The median time to PFS was 9.
40 months, and the 6-month PFS rate was 73.
1%
.
Median OS not reached
.
Based on NGS findings, PIK3CA was the most frequently mutated gene in the cohort, occurring in 13 (31.
7%) patients, including 10 missense mutations
.
9 patients (22.
0%) had FAT1 mutation, followed by PRKDC (8/41, 19.
5%), KMT2D (7/41, 17.
1%) and ATR (6/41, 14.
6%), PIK3CA single gene mutation, PI3K- Mutations in other genes related to the AKT signaling pathway or KMT2D mutations were significantly associated with higher ORR (P < 0.
05)
.
In contrast, STK11 mutation was significantly associated with lower ORR (P < 0.
05)
.
This study is the first prospective anti-PD-1 antibody combined with a multi-kinase inhibitor in the treatment of PD-L1 positive advanced/recurrent cervical cancer, establishing the efficacy of anlotinib combined with sintilimab in the treatment of advanced/recurrent cervical cancer and safety data
.
And the genome-wide analysis of cervical cancer gene mutation map will help to establish a comprehensive evaluation system including multiple biomarkers related to molecular stratified treatment of advanced cervical cancer
.

Image credit: ESMO 2021

In addition to inhibitors targeting immune checkpoints, active immunotherapy for tumors by the host is also constantly being explored and studied
.
Efficacy and safety results of a combination of GX-188E, a therapeutic DNA vaccine, with pembrolizumab, in patients with HPV16 and/or 18-positive advanced cervical cancer reported at the 2021 ASCO Annual Meeting: Phase II KEYNOTE-567 Interim analysis results [7]
.
The study enrolled 54 patients with HPV-16 or HPV-18-positive advanced, surgically incurable, or metastatic cervical cancer who had progressed on standard therapy
.
The study evaluated the efficacy and safety of GX-188E in combination with pembrolizumab
.
According to the investigator's assessment, GX-188E combined with pembrolizumab in the treatment of recurrent cervical cancer who has received multiple treatments in the past has similar safety and tolerability to pembrolizumab monotherapy, and significantly improves the remission rate to 33.
3 % (16/48), PD-L1 positive, HPV16 and squamous cell carcinoma showed higher response rates, among which PD-L1 positive patients were 41.
7%, HPV16 patients were 35.
3%, and squamous cell carcinoma patients were 33.
3% ; Clinical responses were also observed in PD-L1-negative, HPV18 and adenocarcinoma patients
.
Studies have shown that GX-188E combined with pembrolizumab in the treatment of HPV16/18 positive R/M cervical cancer is safe and effective for patients who have failed standard therapy
.

04 HPV cfDNA as a biomarker of response to advanced cervical cancer[8]

04 HPV cfDNA as a biomarker of response to advanced cervical cancer[8] 04 HPV cfDNA as a biomarker of response to advanced cervical cancer[8]

Currently, there are many clinical studies related to cervical cancer immunotherapy, most of which are still in Phase I or Phase II of the trial, and there are few data from Phase III clinical studies
.
Although from the existing data, immunotherapy has achieved encouraging results in the treatment of cervical cancer, its reported overall response rate is immature, and the tumor tissue of most patients with response is positive for PD-L1 expression
.
Therefore, for patients with advanced, recurrent or metastatic cervical cancer, obtaining sufficient and effective tumor tissue samples is still a challenge in the treatment of such patients
.
HPV cell-free DNA (cfDNA) may be a unique tumor marker in advanced cervical cancer, but limited data are available
.
The main objectives of the study included investigating the association between changes in HPV cfDNA and clinical outcomes
.
The study group included 21 patients with metastatic HPV-related cervical cancer, including 17 patients who were receiving treatment and 4 patients who were currently under observation
.
HPV cfDNA genotyping and quantification were performed using Illumina NovaSeq for serial, prospective collection of plasma samples at time points corresponding to changes in clinical outcomes
.
HPV change was defined as a quantifiable increase or decrease in cfDNA levels from baseline in each patient
.
This study also applied a custom ctDNA panel with oncogenic mutations identified by genome sequencing of archived tumors
.

The findings suggest that HPV kinetics remained strongly associated with clinical outcomes in most cases (N=15/21), and HPV levels also occurred when stable disease on imaging was observed (N=4/21).
changes, but further data are needed to confirm whether HPV kinetics can predict changes in outcomes earlier than CT
.
1 patient (007) was completely cleared of HPV and continued to receive treatment without recurrence
.
HPV ctDNA was genotyped, detected, and quantified in all patients at baseline
.
From baseline to first assessment, HPV changes were associated with clinical remission or progression in 17 patients treated (Fisher's exact P=0.
015) and all patients (N=21) treated or observed (Fisher's exact P=0.
001)
.
The custom ctDNA panel was able to detect mutations in 10 cases, which were consistent with those found in the corresponding tumors (excluding 2 cases with insufficient tissue for analysis)
.
Changes in HPV were correlated with changes in Variant Allele Frequency (VAF) when assessed by Spearman's coefficient (rho=0.
83, P=0.
006)
.
The association between clinical changes and changes in VAF was not statistically significant when assessed using Fisher's exact test (P = 0.
05)
.

The results of this preliminary study show that dynamic changes in HPV cfDNA are associated with clinical outcomes in advanced cervical cancer
.
HPV cfDNA has potential applications in non-invasive HPV genotyping and treatment monitoring, but needs to be validated in larger studies
.

To sum up, the treatment of cervical cancer always follows the individualized standard treatment, and the close relationship between HPV virus infection and cervical cancer makes it effective for immunotherapy
.
With the continuous development of precision tumor therapy, existing medical methods and drug treatments will gradually improve the limitations and deficiencies of previous treatment models.
Targeted therapy and immunotherapy have become the "new direction" of cervical cancer treatment
.
In 2021, there are still many bright spots worth reviewing.
The cervical cancer treatment drugs are constantly being developed and developed, and more and more new drug clinical trials have been carried out one after another.
It is expected that more positive results will bring benefits to cervical cancer patients.
, and look forward to the coming 2022.
Relying on precision medicine, it will further guide clinical treatment and bring double improvement of efficacy and quality of life for cervical cancer patients!

Infection precision quality of life

references

1.
Linda R, et al.
Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: ​​The randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274).
Journal of Clinical Oncology, 2021 39: 18_suppl, LBA3-LBA3.

2.
Colombo N, et al.
Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: randomized, double-blind, phase 3 KEYNOTE-826 study.
ESMO Congress, 2021, Abstract LBA2

3.
Tewari KS, et al.
VP4-2021: EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9: Interim analysis of phase III trial of cemiplimab vs.
investigator's choice (IC) chemotherapy (chemo) in recurrent/metastatic (R /M) cervical carcinoma.
ESMO Congress, 2021.

4.
Vergote IB, et al.
Phase I/II trial of tisotumab vedotin plus bevacizumab, pembrolizumab, or carboplatin in recurrent or metastatic cervical cancer (innovaTV 205/ENGOT-cx8).
Annals of Oncology, Volume 30, v433-v434.

5.
O'Malley DM, et al.
LBA34 Single-agent anti-PD-1 balstilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): Preliminary results of two independent phase II trials.
Annals of Oncology, Volume 31, S1164-S1165.

6.
Xu Q, et al.
774P Anlotinib plus sintilimab in patients with recurrent advanced cervical cancer: A prospective, multicenter, single-arm, phase II clinical trial.
Annals of Oncology, Volume 32, S752-S753.

7.
Jong Sup Park, et al.
Efficacy and safety results of GX-188E, a therapeutic DNA vaccine, combined with pembrolizumab administration in patients with HPV 16- and/or 18- positive advanced cervical cancer: Phase II interim analysis results (KEYNOTE -567).
Journal of Clinical Oncology, 2021 39:15_suppl, 5511-5511

8.
McMullen M.
et al.
Circulating human papillomavirus DNA as a biomarker of response in advanced cervical cancer.
Annals of Oncology, Volume 32, S757-S758

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