Cervical cancer is one of the most common gynecological malignancies, second only to breast cancer in incidence. According to the World Health Organization (WHO), there were 604,000 new cases of cervical cancer worldwide in 2020, and about 340,000 women died from the disease. Cervical cancer is often caused by the human papillomavirus (HPV), and other risk factors, such as HIV infection and smoking, can also affect the risk of cervical cancer in a woman infected with HPV. In recent years, with the improvement of public awareness of prevention and the popularization of HPV vaccination, the spread of HPV virus and the corresponding incidence of cervical cancer have been effectively controlled.
According to the data released by the Journal of the National Cancer Center, the incidence of cervical cancer ranks fifth among female malignant tumors in China. For advanced cervical cancer, the effect of chemotherapy is relatively poor, and more effective treatments are needed. In recent years, the emergence of targeted therapy and immunotherapy has brought new hope to patients with advanced cervical cancer. Currently, two targeted therapies and two immunotherapies have been approved clinically for the treatment of advanced cervical cancer.
Targeted Drugs for Cervical Cancer
Targeted drugs refer to drugs that specifically target proteins on cervical cancer cells that help them grow, spread, or live longer, and exert anti-cancer effects by destroying cancer cells or slowing down their growth. Because of their different modes of action, they also have very different side effects from chemotherapy drugs.
1. Drugs targeting tumor angiogenesis - angiogenesis inhibitors
In the process of tumor growth, new blood vessels need to be continuously formed to obtain the nutrients needed for growth. Vascular endothelial growth factor (VEGF) is a key protein that can help tumors form new blood vessels. Targeted drugs against VEGF protein can prevent the formation of tumor new blood vessels by inhibiting the protein function of VEGF and related signaling pathways, thereby effectively curbing tumor growth.
The VEGF-targeted drug commonly used clinically in the treatment of cervical cancer is mainly bevacizumab (trade name: Avastin), which is the first targeted drug approved for cervical cancer. Bevacizumab is a monoclonal antibody that is often used with chemotherapy drugs, and if patients respond to this combination regimen, they can stop chemotherapy and be treated with bevacizumab alone until the cancer returns.
In 2014, the FDA approved bevacizumab (Avastin) in combination with chemotherapy for the treatment of patients with recurrent or advanced (metastatic) cervical cancer. The GOG 240 study showed that combined therapy with targeted drug bevacizumab can significantly improve the overall survival of patients with cervical cancer without causing a decline in the quality of life of patients. At present, bevacizumab has been recommended by the National Comprehensive Cancer Network (NCCN) guidelines as the first choice for the treatment of metastatic cervical cancer. The indication of the drug for cervical cancer has also been approved by the National Medical Products Administration (NMPA).
Bevacizumab may have different side effects than chemotherapy drugs. Some of the more common side effects may include proteinuria, high blood pressure, proteinuria, arterial and venous thromboembolism, cardiovascular toxicity, hemorrhage, intestinal perforation and so on.
2. Antibody drug conjugates
Antibody drug conjugates (ADC) is a drug that combines a chemotherapy drug with a monoclonal antibody. It binds to a specific protein on a cancer cell and delivers the chemotherapy drug to the cancer cell, where it can be targeted.
Currently, tisotumab vedotin (Tivdak) is an ADC for the treatment of cervical cancer. The drug targets a tissue factor (TF) protein on cancer cells and delivers the cytotoxic drug MMAE directly into cancer cells by attaching to the TF protein. It disrupts the microtubule network that divides cancer cells, leading to cell cycle arrest and cell death. In 2021, the FDA granted accelerated marketing approval for Tivdak to treat adult patients with recurrent or metastatic cervical cancer whose disease has progressed during or after chemotherapy. It is worth mentioning that Tivdak is the first and currently only approved ADC drug for cervical cancer. The drug is still being approved for sale in China.
Data from the pivotal Phase II innovaTV 204 study show that tisotumab vedotin is significantly effective as a monotherapy to provide clinically significant and long-lasting objective remission in patients with cervical cancer: The overall response rate (ORR) was 24%, the median duration of response (DOR) was 8.3 months, and the safety was controllable.
Common side effects of Tivdak may include feeling tired, nausea, hair loss, vomiting, bleeding, diarrhea, rash, and nerve damage (peripheral neuropathy). Other common side effects may include abnormalities in blood indicators, such as low red blood cell count (anemia), low white blood cell count, and abnormal kidney function. In addition, patients treated with Tivdak may also experience dry eyes, changes in vision, decreased vision, or corneal ulcers, and patients should have regular eye exams while using this medication.
Immunotherapy for Cervical Cancer
Immunotherapy works by using substances made by the body or in a laboratory to boost the immune system and help the body find and destroy cancer cells. Immunotherapy usually works on specific proteins involved in the action of the immune system to enhance the immune response. Some immunotherapy drugs (such as monoclonal antibodies) work by blocking specific proteins on cancer cells so that they cannot grow, and are therefore sometimes considered to be targeted therapies. Immunotherapies clinically used to treat cervical cancer work primarily by inhibiting immune checkpoints, proteins on immune cells that control the initiation or shutdown of the immune response, and cancer cells sometimes use these checkpoint proteins to avoid being attacked by the immune system, so innovative drugs targeting these proteins can be used in cancer treatment.
1. Pembrolizumab (Keytruda)
The immune checkpoint inhibitor that can be used in the treatment of cervical cancer is pembrolizumab (Keytruda), which targets PD-1. By blocking PD-1, it significantly boosts the immune system's immune response against cancer cells, which can shrink tumors in size or slow their growth. In 2018, Keytruda received accelerated approval from the US FDA for the second-line treatment of patients with recurrent or metastatic cervical cancer, becoming the first PD-1 immunotherapy approved for the treatment of advanced cervical cancer.
Studies in recent years have confirmed that Keytruda also has excellent performance in the field of first-line treatment of cervical cancer, and is expected to become a first-line treatment option for patients with advanced cervical cancer, significantly improving the prognosis of patients with cervical cancer .
2. Cemiplimab (Libtayo)
In November 2022, the European Commission (EC) has approved cemiplimab (Libtayo) as monotherapy for the treatment of adult patients with recurrent or metastatic cervical cancer whose disease has progressed during or after platinum-based chemotherapy.
The approval is mainly based on the results of the phase 3 clinical trial, EMPOWER-Cervical. The results of the study showed that compared with the chemotherapy group, patients treated with Libtayo had significantly improved overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) . Specific data are as follows:
Among all cervical cancer patients, Libtayo reduced the risk of death by 31%, with a median survival of 12.0 months in the Libtayo treatment group and 8.5 months in the chemotherapy group; a 25% reduction in the risk of disease progression; and a more than doubled ORR (16.4% vs 6.3%); the median duration of response (DOR) was significantly prolonged (16.4 months vs 6.9 months).
In patients with squamous cell carcinoma (SCC), Libtayo reduced the risk of death by 27%, with a median survival of 11.1 months in the Libtayo treatment group and 8.8 months in the chemotherapy group; a 29% reduction in the risk of disease progression; and a more than doubling of the ORR (17.6% vs 6.7%).
In patients with adenocarcinoma (AC), Libtayo reduced the risk of death by 44%, with a median survival of 13.3 months in the Libtayo treatment group and 7.0 months in the chemotherapy group; a 9% reduction in the risk of disease progression; and a nearly 3-fold increase in ORR (12 % vs 4%).
Survival with Cemiplimab in Recurrent Cervical Cancer
Possible side effects of immunotherapy drugs include fatigue, fever, nausea, headache, rash, loss of appetite, constipation, joint/muscle pain, and diarrhea. Because these drugs work by removing the "brake" molecules of the body's immune system, they may cause the immune system to attack other parts of the body, causing serious and even life-threatening conditions in a variety of organs, such as the lungs, intestines, liver, hormone-making glands, kidneys, and more. But in general, it's rare.
In recent years, with the development of new therapeutic modalities such as immunotherapy and targeted therapy, new progress has been made in the treatment of cervical cancer, which has significantly improved the prognosis of patients with cervical cancer, especially in cases where traditional chemotherapy-therapy has failed. While these therapies show great promise, they are not without limitations and potential side effects, and further research is still needed to optimize the use of these therapies and identify which patients are most likely to benefit from them.
In general, the emergence of innovative therapies has brought new hope to cervical cancer patients. Due to the space limitation, only a part of cervical cancer treatment methods are introduced here and not all therapies are listed. We'll also be keeping an eye on developments in cancer research and updating readers on the latest treatments.
Polyethylene glycol (PEG) is one of the most widely used linkers in targeted therapies. As a professional manufacturer of pharmaceutical intermediates and PEG linkers, Huateng Pharma is dedicated to being your most reliable partner to provide high-quality PEG linkers for ADC drugs.
 Cervical cancer，Retrieved February 27th, 2023 from https://www.who.int/news-room/fact-sheets/detail/cervical-cancer
 Targeted Drug Therapy for Cervical Cancer，Retrieved February 27th, 2023 from https://www.cancer.org/cancer/cervical-cancer/treating/targeted-therapy.html
 Immunotherapy for Cervical Cancer，Retrieved February 27th, 2023 from https://www.cancer.org/cancer/cervical-cancer/treating/immunotherapy.html