Maintenance phase treatment of ovarian cancer, targeted or immune?

Ovarian cancer is the cancer that causes the highest mortality in women.
65-75% of ovarian cancer patients are already in advanced stages (stage III and IV) at the time of diagnosis, and even after first-line surgery and chemotherapy, stage III or IV The patient's chance of recurrence within two years is still as high as 70-75%, and the 5-year survival rate is less than 30%
.
Therefore, the main purpose of treating recurrent ovarian cancer is to delay the progression of the disease as much as possible
.
Targeted therapies developed in recent years, such as PARP inhibitors (PARP inhibitors, PARPi), angiogenesis inhibitors (angiogenesis inhibitors) and treatments that are still in the research stage, such as Vigil (autologous tumor cell vaccine), CAR-T Therapies, immune checkpoint inhibitors (ICIs), etc.
provide safer and more effective options for improving the efficacy of the maintenance period and reducing toxicity
.
Figure 1.
Global Cancer Observatory PART 01.
Molecular targeted therapy 01BRCA1/2 mutation and PARP inhibitor breast cancer susceptibility genes 1 and 2, the protein encoded by breast cancer susceptibility genes 1 and 2, BRCA1 And BRCA2, is closely related to the body's DNA repair
.
About 15-25% of ovarian cancer patients carry BRCA1/2 germline mutations.
BRCA mutations make the body's genome vulnerable to the accumulation of DNA damage
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PARP is a nuclear protein related to DNA repair, including PARP1, PARP2 and PARP3
.
PARP inhibitors compete with NAD+ for the catalytic domain of PARP and block the formation of DNA repair complexes, thereby removing an important way of DNA repair
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Normal cells can repair DNA through other methods such as BRCA-mediated pathways, but for BRCA-mutated ovarian cancer cells, they are particularly sensitive to PARP inhibitors.
After the genome is damaged, DNA cannot be repaired normally, and mutations accumulate rapidly, resulting in "Synthetic lethal"
.
At present, the FDA has approved 3 PARP inhibitors for the treatment of ovarian cancer, epithelial fallopian tube cancer, and primary peritoneal cancer.
They are olaparib, rucaparib and niraparib ( niraparib), the other two PARP inhibitors, veliparib and talazoparib are in phase III clinical research
.
In general, although PARP inhibitors do have a higher incidence of adverse reactions, especially hematological abnormalities, such as thrombocytopenia, neutropenia and anemia, their toxicity in the body does not accumulate.
After dose adjustment, Security has been proven
.
02 Angiogenesis Inhibitors Angiogenesis refers to the process of forming new capillaries from adjacent blood vessels, which can reshape tissues under pathological conditions such as injury, hypoxia, or normal physiological conditions (such as menstrual cycles)
.
Angiogenesis is very important for the occurrence and development of cancer.
It transports nutrients and removes waste products for fast-growing cancer cells
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Cancer cells secrete pro-angiogenic factors, vascular endothelial growth factor (vascular endothelial growth factor, VEGF) has the most obvious characteristics, and allows these substances to reach the existing blood vessels through the circulatory system and stimulate the abnormal growth of blood vessels
.
Many drugs have been developed for VEGF and its receptors
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Bevacizumab (Avastin?) is a recombinant human monoclonal antibody developed by Genentech.
It targets VEGF to inhibit tumor angiogenesis.
It was approved by the FDA in 2004 and listed in China by the NMPA in 2010.

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In 2014, based on the results of the Phase III Aurelia (NCT00976911) study, compared with the placebo group, the patient's progression-free survival (PFS) was extended from 3.
4 months to 6.
7 after bevacizumab treatment Within months, the objective response rate (ORR) increased from 11.
8% to 27.
3%, and the FDA approved bevacizumab combined with chemotherapy for the treatment of platinum-resistant recurrent ovarian cancer
.
In 2016, the results of Phase III OCEANS (NCT00434642) and GOG-0213 (NCT00565851) studies showed that among the 484 subjects recruited by the former, 407 were ovarian cancer patients.
After treatment with bevacizumab, the PFS of the patients From 8.
4 months to 12.
4 months, the ORR also increased from 57.
4% to 78.
5%; when paclitaxel or carboplatin was used alone in GOG-0213, the patient’s median overall survival (OS) was 37.
3 Months, PFS was 10.
4 months, but after the use of bevacizumab combined with chemotherapy, the median OS was extended to 42.
2 months, and the PFS was extended to 13.
8 months
.
Based on this, bevacizumab was approved, combined with carboplatin and paclitaxel or combined with carboplatin and gemcitabine chemotherapy, for platinum-sensitive recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer
.
In 2018, based on the results of the clinical trial GOG-0218 (NCT00262847), the FDA approved bevacizumab combined with carboplatin and paclitaxel for use in stage III or IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneum after surgical resection Cancer treatment
.
The most common adverse reactions after bevacizumab treatment include headache, nosebleeds, hypertension, and proteinuria.
The less common ones include rhinitis, taste changes, dry skin, exfoliative dermatitis, and rectal bleeding.
Most of the adverse reactions are mild.
Yes, it can be controlled or treated, but you still need to be cautious in the treatment process
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Another ovarian cancer angiogenesis inhibitor drug currently under development is cediranib developed by AstraZeneca.

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Cediranib is a tyrosine kinase inhibitor of VEGF receptor (VEGFR)-1, VEGFR-2, VEGFR-3 and c-kit
.
Phase II clinical studies have shown that patients with recurrent epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer take cediranib daily.
Among them, 30% of the patients (8) have a partial remission, and 6 patients are in stable condition, but none of them are complete.
In remission, the median PFS was 5.
2 months
.
Although these studies show that cediranib is effective in the treatment of ovarian cancer, more clinical trials are still needed to verify its safety and effectiveness
.
Figure 2.
The blood vessel network around the tumor.
Image source: Nature Medicine PART 02.
The current treatment method under development 01 Vigil Vigil is an autologous tumor vaccine, transfected with the gene encoding GM-CSF and bi-shRNA (bifunctional short hairpin RNA) DNA plasmid
.
A phase II clinical study evaluated the safety, immune response, and relapse-free survival (RFS) of Vigil in the maintenance phase of patients with stage III or IV ovarian cancer
.
Of the 42 patients recruited, 31 women received Vigil treatment, and the other 11 received standard treatment
.
The average RFS was extended from 481 days in the control group to 826 days in the Vigil group.
More importantly, there were no reports of adverse reactions in the Vigil group
.
Figure 3.
Comparison of RFS in patients with advanced ovarian cancer treated with standard therapy or Vigil [2] 02 Immune checkpoint inhibitors Immune checkpoints can actually be called the key points for cancer cells to evade the immune system
.
After the immune checkpoint inhibitor enters the body, it can quickly bind to the proteins located on immune cells or cancer cells, so that the immune system has the ability to attack cancer cells again
.
The FDA currently approved 3 types of ICIs.
According to the receptors or ligands they target, they are "CTLA-4" inhibitors (cytotoxic T-lymphocyte associated protein 4) and "PD-1" inhibitors (programmed cell death- 1) and "PD-L1" inhibitor (programmed death ligand-1), the latter two currently seem to be promising immunotherapy drugs in the treatment of malignant tumors
.
T lymphocytes recognize tumor cells through tumor cell surface antigens and stimulate T cell activation.
Activated T cells can synthesize cytokinin, and T cells that have been in an activated state for a long time will produce PD-1.
At the same time, cytokinin Induces cancer cells to produce PD-L1.
After PD-1 binds to PD-L1, it will inhibit the activation of T cells, and cancer cells can escape the attack of the immune system
.
"PD-1" inhibitor and "PD-L1" inhibitor can bind to PD-1 or PD-L1, respectively, thus preventing the binding between PD-1 and PD-L1 and releasing the inhibition of T lymphocytes , T cells can continue to activate and attack tumor cells
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JAVELIN Ovarian 200 (NCT02580058) is the first phase III clinical study evaluating ICIs for the treatment of female ovarian cancer
.
The test is divided into 3 groups, which are PD-L1 inhibitor (avelumab) alone, pegylated liposomal doxorubicin (PLD) alone, and a combination of the two
.
The results of treatment of 566 women with platinum-resistant or refractory/relapsed ovarian cancer, fallopian tube cancer or peritoneal cancer showed that the ORR of patients in the combination group reached 13.
3%, which was higher than that of avelumab alone (3.
6%) or PLD (4.
2%), OS was 15.
7 months, which was longer than 11.
8 months of avelumab and 13.
1 months of PLD.
In addition, the PFS of patients with combination medication was the longest, reaching 3.
7 months, but avelumab or PLD alone was 1.
9 months Months and 3.
5 months
.
Although the combination medication did improve the patients' ORR, OS and PFS, it did not achieve the goal of significantly improving PFS and OS
.
JAVELIN Ovarian 100 Trial (NCT02781417) attempts to evaluate the safety and effectiveness of avelumab in the treatment of ovarian cancer
.
The study recruited 998 patients with stage III/IV ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
They were randomly divided into 3 groups and received (1) carboplatin + paclitaxel; (2) after carboplatin + paclitaxel treatment , Maintenance treatment with avelumab; (3) After avelumab + carboplatin treatment, maintenance treatment with paclitaxel
.
The results of PFS and OS are similar to those of JAVELIN Ovarian 200, but at the beginning of 2019, the trial was declared to have not reached its primary PFS endpoint
.
PART 03.
Conclusion After standard treatment, tumor cytoreductive surgery and platinum-based combined chemotherapy regimens, up to 80% of patients with ovarian cancer will still relapse, and patients with advanced ovarian cancer will experience multiple recurrences.
, Usually cannot be cured
.
Therefore, how to prolong the survival period of patients with ovarian cancer is a problem that needs to be solved urgently
.
Targeted therapies, such as taking PARP inhibitors, are highly targeted and can prolong the PFS of ovarian cancer patients with or without BRCA mutations, but their ability to prolong OS is not satisfactory; immunotherapies such as immune checkpoint inhibitors need to be identified as responding to the inhibitors The biomarkers of PFS and its ability to prolong PFS and OS are limited according to the existing clinical data
.
Nevertheless, targeted therapies and immunotherapy as new tumor treatments still have great potential in the maintenance phase of ovarian cancer.
In a phase II clinical study, olaparib combined with durvalumab (durvalumab) treatment In recurrent ovarian cancer, the patient's disease control rate can reach 81%, and the objective remission rate can reach 63%.
Therefore, immunotherapy combined with anti-angiogenic drugs or PARP inhibitors to prolong the clinical effects of PFS and OS is worthy of in-depth study
.
This article only lists some of the treatment options for the maintenance of ovarian cancer.
If there are any deficiencies, readers are requested to correct them
.
References: 1.
Reynolds, AR et al.
Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors.
Nat Med.
2009, 15 (4), 392-400.
2.
Oh, J.
et al.
Phase II study of Vigil(R) DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer.
Gynecol Oncol.
2016, 143 (3), 504-510.
3.
Drew Y.
et al.
An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): results in germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovarian cancer (OC).
Gynecologic Oncology.
2018, 149: 246-7.
4.
Gogineni, V.
et al.
Current Ovarian Cancer Maintenance Strategies and Promising New Developments.
J Cancer.
2021, 12 (1), 38-53.