Combination of Immunotherapy and Targeted Therapy for Women with Advanced Vulvar Cancer

Vulvar carcinoma is a rare form of cancer that affects the external female genitalia. It most commonly occurs in older women, but can also affect younger patients. The most common type is squamous cell carcinoma, which usually develops from precancerous conditions such as vulvar intraepithelial neoplasia (VIN). This can develop over a period of years. Risk factors include, among others, infection with human papillomavirus (HPV), chronic inflammatory skin conditions such as lichen sclerosus, a weakened immune system, and smoking. Early symptoms may include itching, a burning sensation, hardening, or small lumps in the vulvar area. As the disease progresses, open sores, pain, or bloody discharge may occur. Because the symptoms are nonspecific, many women do not seek medical help until late in the course of the disease, which is why the tumor is often not detected until it has reached an advanced stage. Treatment for vulvar cancer depends on the stage of the disease. In early stages, surgery is often curative. In cases of advanced or recurrent (relapsed) cancer, radiation therapy and chemotherapy may also be necessary. If surgery or radiation therapy is no longer an option, medications such as immunotherapies or targeted therapies can be used to inhibit tumor growth or activate the immune system. The PIERCE study is investigating the combination of pembrolizumab and lenvatinib, drugs already approved for other types of cancer. Pembrolizumab is an immunotherapy that helps the immune system better recognize and fight cancer cells. It blocks a specific receptor on the surface of immune cells—the so-called PD-1 protein—preventing tumor cells from remaining undetected. This blockade allows the immune system to recognize the cancer cells as foreign again and attack them specifically. Lenvatinib is a targeted therapy that interferes with various tumor growth processes. It blocks signaling pathways necessary for the formation of new blood vessels (angiogenesis). Without this blood supply, it is more difficult for the tumor to spread. Since both drugs work differently, the combination could be particularly effective. However, the combination has not yet been approved for VSCC.

The goal of the PIERCE study is to investigate this combined approach of immunotherapy (pembrolizumab) and targeted therapy (lenvatinib) in advanced vulvar carcinoma as well. The study has a single treatment arm, meaning that all patients receive the combination therapy and there is no control group. Pembrolizumab is administered every 6 weeks (every 42 days) as an intravenous infusion. Lenvatinib is taken daily as a tablet. The so-called objective response rate (ORR) is used to assess efficacy. To determine this, researchers evaluate which patients achieve either a partial remission (PR) or a complete remission (CR) within the first 24 weeks after the start of treatment. Partial remission (PR) means that the tumor has shrunk significantly but has not disappeared completely. Complete remission (CR) means that no tumor foci are detectable. Response is assessed using imaging techniques (e.g., CT or MRI). The goal is to determine how many patients respond to the combination therapy.

Women aged 18 and older with histologically confirmed vulvar squamous cell carcinoma (VSCC) are eligible to participate in the study. A prerequisite is that the disease can no longer be treated with curative surgery or definitive (chemotherapy-based) radiation therapy. However, palliative radiation therapy to relieve symptoms is permitted. In addition, patients may have received no more than two prior courses of chemotherapy to treat a recurrence or metastases. Patients who have previously been treated with immune checkpoint inhibitors are excluded.